Phthalazinone derivatives and manufacturing process thereof

ABSTRACT

The present invention relates to phthalazinone derivatives, including pharmaceutical compositions and for the preparation of phthalazinone derivatives. And more particularly the present invention provided a pharmaceutical composition of phthalazinone derivatives for inhibiting activity of the Poly(ADP-riboside) polymerase enzyme.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is the U.S. national phase application filed under 35U.S.C. §371 claiming benefit to International Patent Application No.PCT/KR2014/008523, filed on Sep. 12, 2014, which is entitled to priorityunder 35 U.S.C. §119(a)-(d) to Korea application nos. 10-2013-0110170,filed Sep. 13, 2013 and 10-2014-0120152, filed Sep. 11, 2014, each ofwhich application is hereby incorporated herein by reference in itsentirety.

TECHNICAL FIELD

The present invention relates to phthalazinone derivates, isomers,pharmaceutically acceptable salt thereof and on its study for medicinaluses.

BACKGROUND ART

The interest in Poly ADP ribose polymerase (PARP) inhibitors isincreasing in accordance with the detection of a high rate of BRCA1 orBRCA2 gene mutation due to the recent genetic breast and ovarian cancer.In general, with BRCA genetic mutations the breast cancer risk is 5times higher, and one of them in particular, the probability of aconsiderable risk for TNBC (Triple-negative breast cancer) isincreasing. TNBC accounted for 15% of breast cancer patients is relatedto the lacks of estrogen receptors, progesterone receptors. As there hasbeen no special treatment until now, the target of TNBC containssignificant market potential.

The PARP is the one of repairing enzyme for damaged single-stranded DNAbreakes. In case of inhibition of PARP, the damage of single strandconsecutively generates defects in double-stranded DNA. At this point,the defects of double strand can be recovered by BRCA protein complex.Thus in general, even though the one of the DNA repairing paths is notworking, most of cell can be alive. But the cancer patients whoinheritantly lost repairing path of BRCA protein complex by the mutationof BRCA1/BRCA2 can increase dependancy on the PARP pathway of DNArepairing. Especially, as the possibility of defects in DNA replicationin case of cancer cell is higher than normal cell, the cancer cell hashigher dependance on PARP path than normal cell. In other words, thePARP inhibitors fundamentally block the repairing system of cancer cellfollowing apoptosis of cancer cell.

To date, 18 members of the PARP family have been identified andcharacterized, with PARP-1 being the most thoroughly studied and PARP-2being its closest relative. Despite the large number of enzymes in thisfamily, PARP-1 accounts for >90% of the ADP-ribosylation within thecell. Because of the structural homology between PARP-1 and PARP-2, mostPARP-1 inhibitors also inhibit PARP-2. The PARP-1 enzyme is a 113 kDaprotein with three major structural domains, a DNA binding domain withtwo zinc fingers, a 55 kDa catalytic domain, which utilizes nicotinamideadenine dinucleotide (NAD+) as a substrate to construct polymers ofADP-ribose on histones and other nuclear acceptor proteins including theautomodification domain of PARP-1 itself. It is published and generallyaccepted that the catalytic activity of PARP-1 is stimulated by DNAdamage caused by peroxidation, irradiation, and DNA-damaging chemicals,chemotherapeutic agents. Toward this end, PARP-1 enzyme binds to damagedDNA and stimulates polymerization of ADP-ribose resulting in theunwinding of DNA from histones and exposing the damaged DNA forrepairing. Accordingly, PARP-1 is associated with DNA repairing andmaintenance.

TNBC breast cancer is associated with BRCA1 and BRCA2 gene mutations.The central role of the BRCA gene is the recovery of double strandedbrake (DSB) through homologous recombination (HR). PARP-1 inhibitionwill lead to an increase in single strand breaks (SSB), thepreponderance of these SSBs will eventually lead to increased DSBs. Theincrease of DSBs in BRCA1/BRCA2 gene mutation cancer patients in thepresence of HR deficient cell types leads to chromosomal aberrations andinstability of the genome resulting in cell death.

A conventionally known PARP inhibitor Olaparib (WO2002036576,WO2003093261, US2004876080, US2005059663) are developed for thetreatment of cancer, such as, specifically, stomach cancer, ovariancancer, breast cancer.

Following four patents are published with modified phenyl group ofphthalazinone structure (WO2007138351, WO2007138355, WO2009063244, andWO2009112832).

Since 2011 pharmaceutical companies from China and India publishedvarious patent with modified derivates of Olaparib (WO2012019426A1,WO2012019427A1, WO2012019430A1, WO2012071684A1, WO2012072033A1 andWO2012014221).

As anticancer agents PARP inhibitors, has been progressed with respectto the prior published clinical literature, has a new mechanism ofaction for the treatment of cancer. PARP inhibitors are development asfirst target for personalized medicine based on personal geneticmutation so that worldwide attention is focused. PARP inhibitors havebeen reported to exhibit in particular a significant effect on cancercaused by genetic mutations in BRCA1/2, and the present invention withnew mechanism for the treatment of cancer patients with geneticvariation in BRCA1/2 genes is expected to open a new chapter.

DISCLOSURE OF INVENTION Technical Problem

An object of the present invention is to provide a novel phthalazinonederivative and a process method for preparing.

In addition, the object of the present invention is to provide medicaluse for useful treatment of diseases improved by PARP inhibition, orcancers caused by generic defect of BRCA1, BRCA2, and ERG fusion gene.

However, the technical objects to be achieved in the present inventionare not limited to those stated above and other objects may be clearlyunderstood to those skilled in the art from the following description.

Solution to Problem

To solve the problem described above, the present invention provides acompound represented by Formula I, racemic, enantiomer, diastereoisomerthereof, or pharmaceutically acceptable salt thereof.

wherein,

n is 1 or 2,

R is

Wherein, when the R is

m is 0, 1 or 2,

L is oxygen, methylene, carbonyl, CONHCH₂, NR^(c1)CH₂, NR^(c2)CO,NR^(c3), CONR^(c4) or CH₂NR^(c5) (especially, R^(c1), R^(c2), R^(c3),R^(c4) and R^(c5) is each independently oxygen hydrogen, C₁₋₄alkylamine, C₁₋₆ alkyl, C₁₋₆ alkoxy, halo C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₈ cycloalkyl or 3-8 membered heterocycle),

R^(X) is hydrogen, cyano, hydroxyl, trifluoromethyl, C₁₋₆ alkyl or C₃₋₈cycloalkyl,

R^(Y) is hydrogen, amide, cyano, hydroxyl, trifluoromethyl, halo, ester,C₁₋₄ alkylamine, C₁₋₆ alkyl, C₁₋₆ methoxyalkyl or C₂₋₆ alkynyl,

Z is unsubstituted, C₁₋₆ alkyl, C₁₋₆ methoxyalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, C₆₋₁₀ aromatic cycle or 3-8membered heterocycle having 1-3 nitrogens,

wherein, when the R is

p and q is each independently from 1 to 3,

W is CR^(d1)R^(d2) or NR^(d3) (especially, R^(d1), R^(d2) and R^(d3) iseach independently hydrogen, fluoro or C₁₋₆ alkyl),

wherein, when the R is

R¹, R² and R³ is each independently hydrogen or C₁₋₆ alkyl.

The present invention provides a pharmaceutical composition for treatingcancers comprising the compound represented by Formula I, racemic,enantiomer, diastereoisomer thereof, or pharmaceutically acceptable saltthereof.

The present invention provides a preparation method of the compoundrepresented by Formula I, racemic, enantiomer, diastereoisomer thereof,or pharmaceutically acceptable salt thereof.

Advantageous Effects of Invention

The compounds of the present invention are highly active in thesuppression of PARP, and according to its pharmaceutical compositionsare expected to be useful for therapeutic applications which areimproved by suppression of PARP activity, and cancer with mutated BRCA1,BRCA2 and ERG fusion gene in mono or combination treatment withradiation and with chemotherapy.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail.

The present invention provides a compound represented by Formula I,racemic, enantiomer, diastereoisomer thereof, or pharmaceuticallyacceptable salt thereof.

wherein,

n is 1 or 2,

R is

Wherein, when the R is

m is 0, 1 or 2,

L is oxygen, methylene, carbonyl, CONHCH₂, NR^(c1)CH₂, NR^(c2)CO,NR^(c3), CONR^(c4) or CH₂NR^(c5) (especially, R^(c1), R^(c2), R^(c3),R^(c4) and R^(c5) is each independently oxygen hydrogen, C₁₋₄alkylamine, C₁₋₆ alkyl, C₁₋₆ alkoxy, halo C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₈ cycloalkyl or 3-8 membered heterocycle),

R^(X) is hydrogen, cyano, hydroxyl, trifluoromethyl, C₁₋₆ alkyl or C₃₋₈cycloalkyl,

R^(Y) is hydrogen, amide, cyano, hydroxyl, trifluoromethyl, halo, ester,C₁₋₄ alkylamine, C₁₋₆ alkyl, C₁₋₆ methoxyalkyl or C₂₋₆ alkynyl,

Z is unsubstituted, C₁₋₆ alkyl, C₁₋₆ methoxyalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, C₆₋₁₀ aromatic cycle or 3-8membered heterocycle having 1-3 nitrogens,

wherein, when the R is

p and q is each independently from 1 to 3,

W is CR^(d1)R^(d2) or NR^(d3) (especially, R^(d1), R^(d2) and R^(d3) iseach independently hydrogen, fluoro or C₁₋₆ alkyl),

wherein, when the R is

R¹, R² and R³ is each independently hydrogen or C₁₋₆ alkyl.

In the present invention, the compound of Formula I is preferablyselected form i) or Vii) disclosed below:

i) In case, R is

L is methylene, carbonyl, CONHCH₂, NR^(c1)CH₂, NR^(c2)CO, NR^(c3),CONR^(c4) or CH₂NR^(c5) (especially, R^(c1), R^(c2), R^(c3), R^(c4) andR^(c5) is each independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkynyl orC₃₋₈cycloalkyl), R^(X) is hydrogen, cyano, hydroxyl, trifluoromethyl,methyl, ethyl or cyclopropyl, R^(Y) is hydrogen, dimethylamide, cyano,hydroxyl, trifluoromethyl, halo, ethylester, dimethylamine, methyl,methoxymethyl or propargyl, Z is unsubstituted, C₁₋₆ alkyl, C₁₋₆methoxyalkyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aromatic cycle or 3-8membered heterocycle having 1-3 nitrogens.

ii) In case, R is

p and q is each independently from 1 to 2, W is CR^(d1)R^(d2) or NR^(d3)(especially R^(d1), R^(d2) and R^(d3) is each independently hydrogen,fluoro or methyl).

iii) In case, R is

R¹, R² and R³ is each independently hydrogen, methyl or ethyl.

iv) In case, R is

L is NR^(c1)CH₂, CONR^(c4) or CH₂NR^(c5) (especially, R^(c1), R^(c4) andR^(c5) is each independently hydrogen, methyl, ethyl, propyl, propargylor cyclopropyl),

v) In case, R is

L is methylene or carbonyl, Z is

vi) In case, R is

L is CONHCH₂ or NR^(c2)CO (especially, R^(c2) is hydrogen, methyl, ethylor propyl), Z is

vii) In case, R is

Particularly preferred examples of the compound of Formula I accordingto the present invention comprise the follows:

-   (R)-4-(3-(3-aminopyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-1)-   (S)-4-(3-(3-aminopyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-2)-   4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-3)-   (R)-4-(4-fluoro-3-(3-hydroxypyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-4)-   (S)-4-(4-fluoro-3-(3-hydroxypyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-5)-   4-(4-fluoro-3-(3-hydroxyazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-6)-   4-(4-fluoro-3-(3-(hydroxymethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-7)-   (R)—N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)cyclopropanecarboxamide;    (I-8)-   N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)cyclopropanecarboxamide;    (I-9)-   (S)—N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)cyclopropanecarboxamide;    (I-10)-   (R)—N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)-N-methylcyclopropanecarboxamide;    (I-11)-   N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)-N-methylcyclopropanecarboxamide;    (I-12)-   (S)—N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)-N-methylcyclopropanecarboxamide;    (I-13)-   3-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)-5,5-dimethylimidazolidine-2,4-dione;    (I-14)-   (R)-3-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)imidazolidine-2,4-dione;    (I-15)-   (R)-1-ethyl-3-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)imidazolidine-2,4-dione;    (I-16)-   4-(4-fluoro-3-(3-(4-fluoropiperidine-1-carbonyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-17)-   4-(3-(3-(3,3-difluoroazetidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-18)-   4-(3-(3-(3,3-difluoropyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-19)-   4-(3-(3-(3,3-difluoropyrrolidine-1-carbonyl)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-20)-   (R)—N-(cyclopropylmethyl)-1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidine-3-carboxamide;    (I-21)-   4-(4-fluoro-3-(3-(pyrrolidine-1-carbonyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-22)-   (R)-4-(3-(3-((dimethylamino)pyrrolidine-1-carbonyl)azetidine-1-carbon    yl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-23)-   (S)-4-(3-(3-((dimethylamino)pyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-24)-   4-(3-(3-(cyclobutylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-25)-   4-(3-(3-(cyclopropylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-26)-   4-(3-(3-(cyclopentylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-27)-   4-(3-(3-(cyclohexylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-28)-   (R)-4-(3-(3-(cyclopropylamino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-29)-   (R)-4-(3-(3-(cyclobutylamino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-30)-   (R)-4-(3-(3-(cyclopentylamino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-31)-   4-(4-fluoro-3-(3-(isopropylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-32)-   4-(3-(3-((cyclopropylmethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-33)-   4-(3-(3-(bis(cyclopropylmethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-34)-   4-(4-fluoro-3-(3-(isobutylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-35)-   4-(4-fluoro-3-(3-((1-hydroxypropan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-36)-   4-(4-fluoro-3-(3-(neopentylamino)azetidine-1-carbonyl)benzyl)phthalazin    1(2H)-one; (I-37)-   4-(3-(3-((2,2-dimethylcyclopentyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-38)-   ethyl-   2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)cyclopent-1-enecarboxylate;    (I-39)-   4-(4-fluoro-3-(3-(pentan-3-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-40)-   4-(4-fluoro-3-(3-((3-methylbutan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-41)-   4-(3-(3-((1-cyclopropylethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-42)-   4-(3-(3-(bicyclo[2.2.1]heptan-2-ylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-43)-   4-(3-(3-(sec-butylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-44)-   4-(3-(3-((dicyclopropylmethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-45)-   4-(4-fluoro-3-(3-((4-methylpentan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-46)-   4-(4-fluoro-3-(3-((3-hydroxybutan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-47)-   4-(4-fluoro-3-(3-(pentan-2-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-48)-   4-(4-fluoro-3-(3-((1-(1-methylcyclopropyl)ethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-49)-   4-(4-fluoro-3-(3-((3,3,3-trifluoro-2-methylpropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-50)-   4-(3-(3-(allylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1-(2H)-one;    (I-51)-   4-(4-fluoro-3-(3-(isopentylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-52)-   4-(3-(3-(butylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1-(2H)-one;    (I-53)-   4-(4-fluoro-3-(3-((3-methylbut-2-en-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-54)-   4-(3-(3-((cyclopentylmethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-55)-   4-(4-fluoro-3-(3-((4,4,4-trifluorobutyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-56)-   4-(4-fluoro-3-(3-(pentylamino)azetidine-1-carbonyl)benzyl)phthalazin-1-(2H)-one;    (I-57)-   4-(3-(3-((2-cyclopropylethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-58)-   4-(4-fluoro-3-(3-(propylamino)azetidine-1-carbonyl)benzyl)phthalazin-1-(2H)-one;    (I-59)-   4-(4-fluoro-3-(3-(methyl(pyridin-4-ylmethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-60)-   (R)-4-(4-fluoro-3-(3-(methyl(pyridin-4-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-61)-   (S)-4-(4-fluoro-3-(3-(methyl(pyridin-4-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-62)-   (S)-4-(4-fluoro-3-(3-(methyl(pyridin-2-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-63)-   (R)-4-(4-fluoro-3-(3-(methyl(pyridin-2-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-64)-   4-(4-fluoro-3-(3-(methyl(pyridin-2-ylmethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-65)-   4-(4-fluoro-3-(3-(methyl(pyridin-3-ylmethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-66)-   (S)-4-(4-fluoro-3-(3-(methyl(pyridin-3-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-67)-   (R)-4-(4-fluoro-3-(3-(methyl(pyridin-3-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-68)-   4-(3-(3-(cyclopropyl(methyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-69)-   4-(3-(3-(cyclopropyl(ethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-70)-   4-(3-(3-(cyclobutyl(methyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-71)-   4-(3-(3-(cyclopentyl(prop-2-yn-1-yl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-72)-   4-(3-(3-(3,3-difluoropyrrolidin-1-yl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-73)-   4-(4-fluoro-3-(3-(4-fluoropiperidin-1-yl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-74)-   4-(3-([1,3′-biazetidine]-1′-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-75)-   4-(4-fluoro-3-(3-(pyrrolidin-1-yl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-76)-   4-(4-fluoro-3-(3-(piperidin-1-yl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-77)-   4-(4-fluoro-3-(3-(4-methylpiperazin-1-yl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-78)-   4-(4-fluoro-3-(3-(phenylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-79)-   4-(4-fluoro-3-(3-((1-(trifluoromethyl)cyclopropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-80)-   4-(4-fluoro-3-(3-(prop-2-yn-1-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-81)-   (S)-4-(4-fluoro-3-(3-((1-methoxypropan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-82)-   (R)-4-(4-fluoro-3-(3-((1-methoxypropan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-83)-   4-(4-fluoro-3-(3-((1-(hydroxymethyl)cyclopropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-84)-   4-(4-fluoro-3-(3-((1-methylcyclopropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-85)-   (R)-4-(3-(3-((3,3-dimethylbutan-2-yl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-86)-   (S)-4-(3-(3-((3,3-dimethylbutan-2-yl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-87)-   (R)-4-(4-fluoro-3-(3-((3-methylbutan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-88)-   (S)-4-(4-fluoro-3-(3-((3-methylbutan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-89)-   4-(4-fluoro-3-(3-((1-(methoxymethyl)cyclopropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-90)-   4-(3-(3-(but-3-yn-1-ylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-91)-   4-(4-fluoro-3-(3-((2-methylallyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-92)-   4-(4-fluoro-3-(3-((3-hydroxy-2,2-dimethylpropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-93)-   1-(((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)methyl)cyclopropanecarbonitrile;    (I-94)-   4-(4-fluoro-3-(3-((2,2,2-trifluoroethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-95)-   (R)-4-(4-fluoro-3-(3-(pyrrolidin-3-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-96)-   (S)-4-(4-fluoro-3-(3-(pyrrolidin-3-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-97)-   1-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)cyclopentanecarbonitrile;    (I-98)-   1-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)cyclobutanecarbonitrile;    (I-99)-   2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)propanenitrile;    (I-100)-   2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)butanenitrile;    (I-101)-   2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3    -yl)amino)-3-methylbutanenitrile; (I-102)-   2-cyclopropyl-2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)acetonitrile;    (I-103)-   4-(4-fluoro-3-(3-((1-(trifluoromethyl)cyclobutyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-104)-   (S)-4-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-105)-   (S)-4-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-106)-   4-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-107)-   4-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-108)-   4-(4-fluoro-3-(3-(pyrimidin-2-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-109)-   (S)-4-(4-fluoro-3-(3-(pyrimidin-2-ylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-110)-   (S)-4-(3-(3-((6-chloropyridazin-3-yl)(methyl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-111)-   (S)-4-(3-(3-((6-chloropyridazin-3-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-112)-   (S)-4-(4-fluoro-3-(3-(methyl(pyridazin-3-yl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-113)-   4-(3-(3-((6-chloropyridazin-3-yl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-114)-   4-(3-(3-((6-chloropyridazin-3-yl)(methyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-115)-   4-(3-(3-(cyclobutyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-116)-   4-(4-fluoro-3-(3-(pyridazin-3-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-117)-   (R)-4-(3-(3-((6-chloropyridazin-3-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-118)-   (R)-4-(3-(3-((6-chloropyridazin-3-yl)(methyl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-119)-   (R)-4-(4-fluoro-3-(3-(pyrimidin-2-ylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-120)-   (R)-4-(3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-121)-   (R)-4-(4-fluoro-3-(3-(pyridazin-3-ylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-122)-   (R)-4-(4-fluoro-3-(3-(methyl(pyridazin-3-yl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-123)-   (R)-4-(4-fluoro-3-(3-(thiazol-2-ylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-124)-   (R)-4-(3-(3-((5-ethynylpyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-125)-   (R)-2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)amino)pyrimidine-5-carbonitrile;    (I-126)-   (R)-2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)amino)nicotinonitrile;    (I-127)-   (R)-4-(4-fluoro-3-(3-(pyridin-2-ylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-128)-   (R)-2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)amino)-N,N-dimethylnicotinamiide;    (I-129)-   (R)-4-(3-(3-((5-bromopyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-130)-   (R)-4-(4-fluoro-3-(3-((5-(trifluoromethyl)pyridin-2-yl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-131)-   (R)-4-(4-fluoro-3-(3-((4-(trifluoromethyl)pyridin-2-yl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-132)-   4-(3-(3-(benzylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-133)-   4-(4-fluoro-3-(3-((3,3,3-trifluoropropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-134)-   (R)-4-(3-(3-(azetidin-1-yl)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-135)-   (R)-4-(3-([1,3′-bipyrrolidine]-1′-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-136)-   (R)-4-(4-fluoro-3-(3-(piperidin-1-yl)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-137)-   (R)-4-(4-fluoro-3-(3-(p-tolylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-138)-   (R)-4-(4-fluoro-3-(3-(phenylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-139)-   4-(4-fluoro-3-(3-(pyrrolidin-1-ylmethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-140)-   4-(4-fluoro-3-(3-(piperidin-1-ylmethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-141)-   4-(3-(3-(azetidin-1-ylmethyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-142)-   4-(3-(3-((cyclopropylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-143)-   4-(4-fluoro-3-(3-((isopropylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-144)-   4-(3-(3-(((cyclopropylmethyl)amino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-145)-   4-(4-fluoro-3-(3-((isobutylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-146)-   4-(3-(3-((tert-butylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-147)-   4-(3-(3-((cyclobutylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-148)-   4-(4-fluoro-3-(3-((prop-2-yn-1-ylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-149)-   4-(4-fluoro-3-(3-((phenylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;    (I-150)-   1-((((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)methyl)amino)methyl)cyclopropanecarbonitrile;    (I-151)-   1-(((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)methyl)amino)cyclopropanecarbonitrile;    (I-152)-   4-(3-(3-((cyclopropyl(prop-2-yn-1-yl)amino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-153)-   4-(3-(3-((cyclopropyl(methyl)amino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;    (I-154)-   4-(3-(3-((cyclopropyl(ethyl)amino)methyl)azetidine-1-carbonyl)-4-fluoro    benzyl)phthalazin-1(2H)-one; (I-155)-   4-(3-(3-(cyclobutylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one    hydrochloride; (I-156)-   4-(3-(3-(cyclopropylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one    hydrochloride; (I-157)-   4-(3-(3-(cyclopentyl    amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one    hydrochloride; (I-158)-   4-(4-fluoro-3-(3-(isopropylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one    hydrochloride; (I-159)-   4-(3-(3-((cyclopropylmethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one    hydrochloride; (I-160)-   4-(4-fluoro-3-(3-(isobutylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one    hydrochloride; (I-161)-   4-(4-fluoro-3-(3-((1-hydroxypropan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one    hydrochloride; (I-162)-   4-(3-(3-(butylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one    hydrochloride; (I-163)-   4-(3-([1,3′-biazetidine]-1′-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one    hydrochloride; (I-164)-   (R)-4-(4-fluoro-3-(3-((1-methoxypropan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one    hydrochloride; (I-165)-   1-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)cyclobutanecarbonitrile    hydrochloride; (I-166)-   (R)-4-(3-(3-(azetidin-1-yl)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one    hydrochloride; (I-167)-   4-(4-fluoro-3-(3-(pyrrolidin-1-ylmethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one    hydrochloride; (I-168)-   4-(4-fluoro-3-(3-(piperidin-1-ylmethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one    hydrochloride; (I-169)-   4-(3-(3-(azetidin-1-ylmethyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one    hydrochloride; (I-170)-   4-(3-(3-((cyclopropylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one    hydrochloride; (I-171)-   4-(4-fluoro-3-(3-((isopropylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one    hydrochloride; (I-172)-   4-(3-(3-(((cyclopropylmethyl)amino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one    hydrochloride; (I-173)-   4-(4-fluoro-3-(3-((isobutylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one    hydrochloride; (I-174)-   4-(3-(3-((cyclobutylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one    hydrochloride; (I-175) and-   4-(4-fluoro-3-(3-((prop-2-yn-1-ylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one    hydrochloride; (I-176).

In the present invention, “C₁₋₄ alkylamine” is a saturated hydrocarbonylamine with linear or branched chains of 1-4 carbon atoms. Exemplaryalkylamines include, but are not limited, to methylamine, ethylamine,propylamine, butylamine, 1-methylethylamine, diethylamine ordimethylamine.

In the present invention, “C₁₋₆ alkyl” is a saturated hydrocarbonylamine with linear or branched chains of 1-6 carbon atoms. Exemplaryalkyl include, but are not limited, to methyl, ethyl, propyl, butyl,pentyl, hexyl, 1-methylethyl, 1-methylpropyl, 2-methylpropyl,1,1-dimethylethyl, 1-methylbutyl, 1,1-dimethylpropyl, 1-methylpentyl or1,1-dimethylbutyl.

In the present invention, “C₁₋₆alkoxy” is an OR group with R as definedabove. Exemplary alkoxy with 1-6 carbon atoms include, but are notlimited, to methoxy, ethoxy, propoxy, butoxy, 1-methylethoxy,1,1-dimethylethoxy, 1-methylpropoxy, 2-methylpropoxy orcyclopropylmethoxy.

In the present invent ion, “halo C₁₋₆alkyl” is intended as a C₁₋₆alkylradical having one or more hydrogen atoms replaced by a halogen atomsdefined above. Exemplary haloalkyl include, but are not limited, todifluoromethyl or trifluoromethyl.

In the present invention, “halo” is intended as bromine, fluorine, orchlorine atom.

In the present invent ion, “C₂₋₆ alkenyl” is intended as a linear orbranched hydrocarbonyl chain of 2-6 carbon atoms and at least onecarbon-carbon double bond. Alkenyls have a “cis” or “trans” and “E” or“Z” double bond configuration. Exemplary alkenyl include, but are notlimited, to crotyl (—CH₂CH═CHCH₃), vinyl (—CH═CH₂) or allyl(—CH₂CH═CH₂).

In the present invention, “C₂₋₆ alkynyl” is intended as a linear orbranched hydrocarbonyl radical with 2-6 carbon atoms and at least onecarbon-carbon triple bond. Exemplary alkynyl include, but are notlimited, to ethynyl(—C≡CH) or propargyl (—CH₂C≡CH).

In the present invention, “C₃₋₈ cycloalkyl” is intended as a saturatedhydrocarbonyl ring with 3-8 carbon atoms. Exemplary cycloalkyl include,but are not limited, to cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl.

In the present invention, “C₃₋₈ cycloalkenyl” is intended as anunsaturated hydrocarbonyl ring with 3-8 carbon atoms and at least onecarbon-carbon double bond. Alkenyls have a “cis” or “trans” and “E” or“Z” double bond configuration. Exemplary cycloalkenyl include, but arenot limited, to cyclopropenyl, cyclobutenyl, cyclopentenyl,cyclohexenyl, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptenyl,cyclooctenyl or 1,5-cyclooctadiene.

In the present invention, “C₆₋₁₀ aromatic cycle” is intended as anaromatic hydrocarbonyl radical with 6-10 carbon atoms. Exemplaryaromatic ring include, but are not limited, to phenyl or naphthyl.

In the present invention, “heterocycle” is intended as a saturated orpartially unsaturated hydrocarbonyl mono-tricyclic ring with at leastone nitrogen atom. Exemplary mono heterocycles with 5-6 atoms include,but are not limited, to pyrrolidinyl, piperidinyl, pyrollyl, pyrazolyl,imidazolyl, oxazolyl, isoxazolyl, triazolyl, thiazolyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl. Also, exemplarybicyclic aromatic ring include, but are not limited, to benzothiazolyl,benzoxazolyl, benzoxazinone, benzoxadiazolyl, 1,3-benzodioxolyl,benzofuryl, benzopyrazinyl, indolyl, indazolyl, benzimidazolyl,benzopyranyl, pyrolopyridanyl, furopyridinyl, or imidazothiazolyl.

The term “pharmaceutically acceptable,” as used herein, when referringto a component of a pharmaceutical composition means that the component,when administered to an animal, does not have undue adverse effects suchas excessive toxicity, irritation, or allergic response commensuratewith a reasonable benefit/risk ratio.

The term “treatment” as used herein covers any treatment of a disease ina mammal, particularly a human, and includes inhibiting the disease,i.e., arresting its development; or relieving the disease, i.e. causingregression of the disease and/or its symptoms or conditions and slowingdisease progression.

The term “therapeutically effective amount” means an amount of acompound of the present invention that ameliorates, attenuates oreliminates a particular disease or condition or prevents or delays theonset of a particular disease or condition. In the case of cancer, thetherapeutically effective amount of the drug may reduce the number ofcancer cells; reduce the tumor size; inhibit (i.e., slow to some extentand preferably stop) cancer cell infiltration into peripheral organs;inhibit (i.e., slow to some extent and preferably stop) tumormetastasis; inhibit, to some extent, tumor growth; and/or relieve tosome extent one or more of the symptoms associated with the cancer. Tothe extent the drug may prevent growth and/or kill existing cancercells, it may be cytostatic and/or cytotoxic.

The compounds of the invention may contain asymmetric or chiral centers,and therefore exist in different stereoisomeric forms. It is intendedthat all stereoisomeric forms of the compounds of the invention,including but not limited to, diastereomers, enantiomers andatropisomers, as well as mixtures thereof such as racemic mixtures, formpart of the present invention. A specific stereoisomer may also bereferred to as an enantiomer, and a mixture of such isomers is oftencalled an enantiomeric mixture. A 50:50 mixture of enantiomers isreferred to as a racemic-mixture or a racemate.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g. melting points,boiling points, spectral properties, and reactivities. Mixtures ofdiastereomers may separate under high resolution analytical proceduressuch as electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

The phrase “pharmaceutically acceptable salt” as used herein, refers topharmaceutically acceptable organic or inorganic salts of a compound ofthe invention. Exemplary salts include, but are not limited, to sulfate,citrate, acetate, oxalate, chloride, bromide, iodide, nitrate,bisulfate, phosphate, acid phosphate, isonicotinate, lactate,salicylate, citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucuronate, saccharate, formate, benzoate, glutamate,methanesulfonate “mesylate”, ethanesulfonate, benzenesulfonate,p-toluenesulfonate, and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. A pharmaceuticallyacceptable salt may involve the inclusion of another molecule such as anacetate ion, a succinate ion or other counter ion. The counter ion maybe any organic or inorganic moiety that stabilizes the charge on theparent compound. Furthermore, a pharmaceutically acceptable salt mayhave more than one charged atom in its structure. Instances wheremultiple charged atoms are part of the pharmaceutically acceptable saltcan have multiple counter ions. Hence, a pharmaceutically acceptablesalt can have one or more charged atoms and/or one or more counter ion.

If the compound of the invention is a base, the desired pharmaceuticallyacceptable salt may be prepared by any suitable method available in theart, for example, treatment of the free base with an inorganic acid,such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,methane-sulfonic acid, phosphoric acid and the like, or with an organicacid, such as acetic acid, maleic acid, succinic acid, mandelic acid,fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,salicylic acid, a pyranosidyl acid, such as glucuronic acid orgalacturonic acid, an alpha hydroxy acid, such as citric acid ortartaric acid, an amino acid, such as aspartic acid or glutamic acid, anaromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid,such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.

If the compound of the invention is an acid, the desiredpharmaceutically acceptable salt may be prepared by any suitable method,for example, treatment of the free acid with an inorganic or organicbase, such as an amine (primary, secondary or tertiary), an alkali metalhydroxide or alkaline earth metal hydroxide, or the like. Illustrativeexamples of suitable salts include, but are not limited to, organicsalts derived from amino acids, such as glycine and arginine, ammonia,primary, secondary, and tertiary amines, and cyclic amines, such aspiperidine, morpholine and piperazine, and inorganic salts derived fromsodium, calcium, potassium, magnesium, manganese, iron, copper, zinc,aluminum and lithium.

In another aspect, the present invent ion provides a method of preparingthe compound represented by Formula I or a pharmaceutically approvedsalt thereof.

A preparation method of the present invention is shown in the following.

The compound of Formula I of the present invention, as shown in Scheme1, can be prepared by series of steps from the compound of Formula 2.

n and R, illustrated in Scheme 1, are defined as below:

Wherein,

n is 1 or 2;

R is

Wherein, when the R is,

m is 0, 1 or 2,

L is oxygen, methylene, carbonyl, CONHCH₂, NR^(c1)CH₂, NR^(c2)CO,NR^(c3), CONR^(c4) or CH₂NR^(c5) (especially, R^(c1), R^(c2), R^(c3),R^(c4) and R^(c5) is each independently oxygen hydrogen, C₁₋₄alkylamine, C₁₋₆ alkyl, C₁₋₆ alkoxy, halo C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₈ cycloalkyl or 3-8 membered heterocycle),

R^(X) is hydrogen, cyano, hydroxyl, trifluoromethyl, C₁₋₆ alkyl or C₃₋₈cycloalkyl,

R^(Y) is hydrogen, amide, cyano, hydroxyl, trifluoromethyl, halo, ester,C₁₋₄ alkylamine, C₁₋₆ alkyl, C₁₋₆ methoxyalkyl or C₂₋₆ alkynyl,

Z is unsubstituted, C₁₋₆ alkyl, C₁₋₆ methoxyalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, C₆₋₁₀ aromatic cycle or 3-8membered heterocycle having 1-3 nitrogens,

wherein, when the R is

p and q is each independently from 1 to 3,

W is CR^(d1)R^(d2) or NR^(d3) (especially, R^(d1), R^(d2) and R^(d3) iseach independently hydrogen, fluoro or C₁₋₆alkyl),

wherein, when the R is

R¹, R² and R³ is each independently hydrogen or C₁₋₆ alkyl.

The preparation method of the Formula I comprise:

Preparing a compound of Formula 4 from a compound of Formula 2 and 3which reacted with amide coupling reaction (Step 1)

Preparing a compound of Formula 6 from a compound of Formula 4 and 5which reacted with olefination reaction (Step 2)

Preparing a compound of Formula I from a compound of Formula 6 andhydrazine monohydrate which reacted with condensation reaction (Step 3)

Each step of the above preparation method is described in more detail asfollows.

i) The compound of Formula 4 can be prepared from Formula 2 by amidecoupling in the above Step 1. An Amide coupling reaction is carried outwith 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI)and 4-(Dimethylamino)pyridine (DMAP) orO-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU) and N,N-diisopropyl ethylamine (DIPEA). Examples of solventsuseful in the react ion include chloroform or dimethyl formamide. Thereaction is heated to 20˜35° C. for 1˜30 hours, so as to obtain thecompound of Formula 4.

Example of preparing the compound of Formula 4 from the compound ofFormula 2 and 3 by amide coupling in the above Step 1 is illustratedbelow.

ii) The compound of Formula 6 can be prepared from Formula 4 byolefination in the above Step 2. An olefination reaction is carried outwith Formula 5 in basic condition. Examples of solvent useful in thereaction include THF. The reaction is cooled to 0° C. for 1˜5 hours, soas to abtain the compound of Formula 6.

Example of preparing the compound of Formula 6 from the compound ofFormula 4 and 5 by olefination in the above Step 2 is illustrated below.

iii) The compound of Formula I can be prepared from Formula 6 bycondensation in the above Step 3. A condensation reaction is carried outwith hydrazine monohydrate. Example of solvent useful in the react ionincludes water. The react ion is heated to 30˜70° C. for 20 hours, so asto obtain the compound of Formula I.

Example of preparing the compound of Formula I from the compound ofFormula 6 by condensation in the above Step 3 is illustrated below.

In another aspect, the present invention provides another method ofpreparing the compound represented by Formula I or a pharmaceuticallyapproved salt thereof.

Besides, another preparation method of the present invention is shown inthe following.

The compound of Formula I of the present invention, as shown in Scheme2, can be prepared by series of steps from the compound of Formula 1.

n, R₄ and R, illustrated in Scheme 2, are defined as below:

Wherein,

n is 1 or 2;

R₄ and R₅ is each independently tert-butyldimethylsiloxyl

tert-butyldimethylsiloxymethyl

benzylcarbamate, amine, CH₂OH or hydroxyl;

R is

wherein, when the R is

m is 0, 1 or 2,

L is oxygen, methylene, carbonyl, CONHCH₂, NR^(c1)CH₂, NR^(c2)CO,NR^(c3), CONR^(c4) or CH₂NR^(c5) (especially, R^(c1), R^(c2), R^(c3),R^(c4) and R^(c5) is each independently oxygen hydrogen, C₁₋₄alkylamine, C₁₋₆ alkyl, C₁₋₆ alkoxy, halo C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₈ cycloalkyl or 3-8 membered heterocycle),

R^(X) is hydrogen, cyano, hydroxyl, trifluoromethyl, C₁₋₆ alkyl or C₃₋₈cycloalkyl,

R^(Y) is hydrogen, amide, cyano, hydroxyl, trifluoromethyl, halo, ester,C₁₋₄ alkylamine, C₁₋₆ alkyl, C₁₋₆ methoxyalkyl or C₂₋₆ alkynyl,

Z is unsubstituted, C₁₋₆ alkyl, C₁₋₆ methoxyalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, C₆₋₁₀ aromatic cycle or 3-8membered heterocycle having 1-3 nitrogens,

wherein, when the R is

p and q is each independently from 1 to 3,

W is CR^(d1)R^(d2) or NR^(d3) (especially, R^(d1), R^(d2) and R^(d3) iseach independently hydrogen, fluoro or C₁₋₆alkyl),

wherein, when the R is

R¹, R² and R³ is each independently hydrogen or C₁-₆alkyl.

Another preparation method of the Formula I comprises

Preparing a compound of Formula 8 from a compound of Formula 7 and 3which reacted with amide coupling reaction (Step 1)

Preparing a compound of Formula 9 from a compound of Formula 8 and 5which reacted with olefination reaction (Step 2)

Preparing a compound of Formula 10 from a compound of Formula 9 andhydrazine monohydrate which reacted with condensation reaction (Step 3)

Preparing a compound of Formula 11 from a compound of Formula 10 whichreacted with carboxybenzyl or tertbutyldimethylsiloxyl

deprotection reaction (Step 4)

Preparing a compound of Formula I from a compound of Formula 11 whichreacted with amide coupling, substitution and reductive aminationreaction (Step 5)

Each step of the above preparation method is described in more detail asfollows.

i) The compound of Formula 8 can be prepared from Formula 7 by amidecoupling in the above Step 1. An Amide coupling reaction is carried outwith 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI)and 4-(Dimethylamino)pyridine (DMAP) orO-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU) and N,N-diisopropyl ethylamine (DIPEA). Examples of solventsuseful in the react ion include chloroform or dimethyl formamide. Thereact ion is heated to 20˜35° C. for 1˜30 hours, so as to obtain thecompound of Formula 8.

Example of preparing the compound of Formula 8 from the compound ofFormula 7 and 3 by amide coupling in the above Step 1 is illustratedbelow.

ii) The compound of Formula 9 can be prepared from Formula 8 byolefination in the above Step 2. An olefination reaction is carried outwith Formula 5 in basic condition. Examples of solvent useful in thereaction include THF. The reaction is cooled to 0° C. for 1˜5 hours, soas to abtain the compound of Formula 9.

Example of preparing the compound of Formula 9 from the compound ofFormula 8 and 5 by olefination in the above Step 2 is illustrated below.

iii) The compound of Formula 10 can be prepared from Formula 9 bycondensation in the above Step 3. A condensation reaction is carried outwith hydrazine monohydrate. Example of solvent useful in the reactionincludes water. The reaction is heated to 30˜70° C. for 20 hours, so asto obtain the compound of Formula 10.

Example of preparing the compound of Formula 10 from the compound ofFormula 9 by condensation in the above Step 3 is illustrated below.

iv) The compound of Formula 11 can be prepared from Formula 10 bycarboxybenzyl or tert-butyloxycarbonyl

deprotection in the aboveStep 4. A carboxybenzyl or tert-butyldimethylsiloxyl

deprotection reaction is carried out with Pd/C under N₂ gas or 1Msolution of tetra-n-butylammonium fluoride in THF (TBAF), so as toobtain the compound of Formula 11.

Example of preparing the compound of Formula 11 from the compound ofFormula 10 by condensation in the above Step 4 is illustrated below.

v) The compound of Formula I can be prepared from Formula 11 by amidecoupling, substitution and reductive amination reaction.

A step 5 of the Scheme 2 is described in more detail as follows.

In Step 5 of the preparation method, the compound of Formula I can beprepared with amide coupling, substitution and reductive amination.

In the above amide coupling reaction, the reaction is carried out with1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) and4-(Dimethylamino)pyridine (DMAP) orO-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU) and N,N-diisopropyl ethylamine (DIPEA). Examples of solventsuseful in the react ion include chloroform or dimethylformamide, so asto obtain the compound of Formula I. An example is illustrated below.

Besides, In the Step 5, the compound of Formula I can be prepared withfrom substitution.

In the above substitution reaction, mesylate compound is prepared fromalcohol compound by reaction with methanesulfonyl chloride indichloromethane. And then, desired functional group can be introduced byreaction of mesylate compound with

(In above Scheme, p, q, m, W, Z, R^(X) and R^(Y), are the same asdefined in Formula I). An example of preparing the compound of Formula Iform the compound of Formula 8 by substitution in the present inventionis illustrated below (The R^(c6) substitution is introduced with K₂CO₃and R^(c6)—I).

Besides, in the above reductive amination react ion, the compound ofFormula I can be prepared form

(In above Scheme, m, Z, R^(X) and R^(Y), are the same as defined inFormula I). The reaction is carried out with sodiumtriacetoxyborohydride and acetic acid for overnight. Examples of solventuseful in the reaction include chloroform or dichloromethane. An exampleof preparing the compound of Formula I is illustrated below (The R^(c4)substitution is introduced with K₂CO₃ and R^(c4)—I indimethylformamide).

In addition, the present invention provides a pharmaceutical ompositionfor treating cancers comprising the compound of Formula I, racemic,enantiomer, diastereoisomer thereof, or pharmaceutically acceptable saltthereof. The cancers may be caused by PARP activity, or generic defectof BRCA1, BRCA2, and ERG fusion gene. Exemplary cancers include, but arenot limited to breast cancer, ovarian cancer, pancreatic cancer, gastriccancer, lung cancer, colorectal cancer, brain tumor, prostate cancer andEwings sarcoma. As used herein, the term “generic defect” is intended asgene mutation, gene deficiency or defect of gene expression, but is notlimited thereto.

The present invention provides a method of treating cancers in a subjectin need thereof, comprising administering an effective amount of thepharmaceutical composition to the subject. The dosage of pharmaceuticalcomposition of the present invention may vary depending on the patient'sweight, age, gender, physical condition, diet, the time and mode ofadministration, excretion rates, and the severity of illness. Mammals(including human) are desirable for the individual without limit.

Compounds of the invention intended for pharmaceutical use may beadministered as a solid or liquid, such as a tablet, capsule, solutionor suspension. Pharmaceutical compositions suitable for the delivery ofcompounds of the present invention and methods for their preparationwill be readily apparent to those skilled in the art. Such compositionsand methods for their preparation may be found, for example, inRemingtons Pharmaceutical Sciences, 19th Edition (Mack PublishingCompany, 1995).

The present invention provides compound, specifically, active ininhibiting the activity of PARP. Compounds of the invention can be usedin cancer treatment through inhibition of PARP. Exemplary include lungcancer, gastrointestinal cancer, prostate cancer, uterine cancer, orespecially breast cancer, or ovarian cancer.

Compounds of the invent ion may be combined in a pharmaceuticalcombination formulation, or dosing regimen as combination therapy, witha second compound having anti-cancer properties or at least two kinds ofpharmaceutical active ingredients.

The examples of agents include: oxaliplatin (ELOXATIN®, Sanofi),bortezomib (VELCADE®, Millennium Pharm.), sutent (SUNITINIB®, SU11248,Pfizer), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®,Novartis), XL-518 (Mek inhibitor, Exelixis, WO 2007/044515), ARRY-886(Mek inhibitor, AZD6244, Array Bio-Pharma, Astra Zeneca), SF-1126 (PI3Kinhibitor, Semafore Pharmaceuticals), BEZ-235 (PI3K inhibitor,Novartis), XL-147 (PI3K inhibitor, Exelixis), PTK787/ZK 222584(Novartis), fulvestrant (FASLODEX®, AstraZeneca), leucovorin (folinicacid), rapamycin (sirolimus, RAPAMUNE®, Wyeth), lapatinib (TYKERB®,GSK572016, Glaxo Smith Kline), lonafarnib (SARASAR®, SCH 66336, ScheringPlough), sorafenib (NEXAVAR®, BAY43-9006, Bayer Labs), gefitinib(IRESSA®, AstraZeneca), irinotecan (CAMPTOSAR®, CPT-11, Pfizer),tipifarnib (ZARNESTRA®, Johnson & Johnson), ABRAXANE® (Cremophor-free),albumin-engineered nanoparticle formulations of paclitaxel (AmericanPharmaceutical Partners, Schaumberg, 1H), vandetanib (rINN, ZD6474,ZACTIMA®, AstraZeneca), chloranmbucil, AG1478, AG1571 (SU 5271; Sugen),temsirolimus (TORISEL®, Wyeth), pazopanib (GlaxoSmithKline),canfosfamide (TELCYTA®, Telik), thiotepa and cyclosphosphamide(CYTOXAN®, NEOSAR®); alkyl sulfonates such as busulfan, improsulfan andpiposulfan; aziridines such as benzodopa, carboquone, meturedopa, anduredopa; ethylenimines and methylamelamines including altretamine,triethylenemelamine, triethylenephosphoramide,triethylenethiophosphoramide and trimethylomelamine; acetogenins(especially bullatacin and bullatacinone); a camptothecin (including thesynthetic analog topotecan); bryostatin; callystatin; CC-1065 (includingits adozelesin, carzelesin and bizelesin synthetic analogs);cryptophycins (particularly cryptophycin 1 and cryptophycin 8);dolastatin; duocarmycin (including the synthetic analogs, KW-2189 andCB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin;nitrogen mustards such as chlorambucil, chlornaphazine,chlorophosphamide, estramustine, ifosfamide, mechlorethamine,mechlorethamine oxide hydrochloride, melphalan, novembichin,phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureassuch as carmustine, chlorozotocin, fotemustine, lomustine, nimustine,and ranimnustine; antibiotics such as the enediyne antibiotics (e.g.,calicheamicin, calicheamicin gamma II, calicheamicin omega II (AngewChem. Intl. Ed. Engl. (1994) 33:183-186); dynemicin, dynemicin A;bisphosphonates, such as clodronate; an esperamicin; as well asneocarzinostatin chromophore and related chromoprotein enediyneantibiotic chromophores), aclacinomysins, actinomycin, authramycin,azaserine, bleomycins, cactinomycin, carabicin, caminomycin,carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin,6-diazo-5-oxo-L-norleucine, morpholino-doxorubicin,cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin anddeoxydoxorubicin), epirubicin, esorubicin, idarubicin, nemorubicin,marcellomycin, mitomycins such as mitomycin C, mycophenolic acid,nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogs such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine;androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil;amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid;gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids suchas maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol;nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone;podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK polysaccharidecomplex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin;sizofuran; spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethylamine; trichothecenes (especially T-2 toxin,verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; 6-thioguanine;mercaptopurine; methotrexate; platinum analogs such as cisplatin andcarboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone;vincristine; vinorelbine (NAVELBINE®); novantrone; teniposide;edatrexate; daunomycin; aminopterin; capecitabine (XELODA®, Roche);ibandronate; CPT-11; topoisomerase inhibitor RFS 2000;difluoromethylornithine (DMFO); retinoids such as retinoic acid; andpharmaceutically acceptable salts, acids and derivatives of any of theabove.

For instance, compounds of the invention, especially formula I orpharmaceutically acceptable salt can be administered simultaneously,gradually, or individually with at least one of therapeutic agents.

Oral Administration

In one embodiment, the compounds of the invent ion may be administeredorally. Oral administration may involve swallowing, so that the compoundenters the gastrointestinal tract, and/or buccal, lingual, or sublingualadministration by which the compound enters the blood stream directlyfrom the mouth.

Formulations suitable for oral administration include solid plugs, solidmicroparticulates, semi-solid and liquid (including multiple phases ordispersed systems) such as tablets; soft or hard capsules containingmulti- or nanoparticulates, liquids, emulsions or powders; lozenges(including liquid-lled); chews; gels; fast dispersing dosage forms; lms;ovules; sprays; and buccal/mucoadhesive patches. Liquid (includingmultiple phases and dispersed systems) formulations include emulsions,suspensions, solutions, syrups and elixirs. Such formulations may bepresented as llers in soft or hard capsules (made, for example, fromgelatin or hydroxypropylmethylcellulose) and typically comprise acarrier, for example, water, ethanol, polyethylene glycol, propyleneglycol, methylcellulose, or a suitable oil, and one or more emulsifyingagents and/or suspending agents. Liquid formulations may also beprepared by the reconstitution of a solid, for example, from a sachet.

The compounds of the invention may also be used in fast-dissolving,fast-disintegrating dosage forms such as those described in ExpertOpinion in Therapeutic Patents, 11 (6), 981-986 by Liang and Chen(2001).

The immediate release portion may comprise a disintegrant. Examples ofdisintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethyl cellulose, croscarmellose sodium,crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystallinecellulose, powdered cellulose, lower alkyl-substituted hydroxypropylcellulose, polacrilin potassium, starch, pregelatinized starch, sodiumalginate, and mixtures thereof. Generally, the disintegrant willcomprise from 1 wt % to 80 wt %, preferably from 5 wt % to 60 wt % ofthe layer.

Examples of matrix materials, fillers, or diluents include lactose,mannitol, xylitol, dextrose, sucrose, sorbitol, compressible sugar,microcrystalline cellulose, powdered cellulose, starch, pregelatinizedstarch, dextrates, dextran, dextrin, dextrose, maltodextrin, calciumcarbonate, dibasic calcium phosphate, tribasic calcium phosphate,calcium sulfate, magnesium carbonate, magnesium oxide, poloxamers,polyethylene oxide, hydroxypropyl methyl cellulose and mixtures thereof.

When preparing dosage forms incorporating the compositions of the invention, the compounds may also be blended with conventional excipients suchas binders, including gelatin, pregelatinized starch, and the like;lubricants, such as hydrogenated vegetable oil, stearic acid, and thelike; diluents, such as lactose, mannose, and sucrose; disintegrants,such as carboxymethylcellulose and sodium starch glycolate; suspendingagents, such as povidone, polyvinyl alcohol, and the like; absorbants,such as silicon dioxide; preservatives, such as methylparaben,propylparaben, and sodium benzoate; surfactants; such as sodium laurylsulfate, polysorbate 80, and the like; flavorants; and sweeteners. Ifpresent, the surfactants would comprise of 0.2 wt % to 5 wt % and theabsorbants would comprise from 0.2 wt % to 1 wt %. Another excipientsinclude one or more of: anti-oxidants, colourants, flavouring agents,preservatives and taste-masking agents.

Tablet blends or portions of blends may alternatively be wet-, dry-, ormelt-granulated, melt congealed, or extruded before tabletting. Thefinal formulation may comprise one or more layers and may be coated oruncoated; it may even be encapsulated.

The formulation of tablets is discussed in “Pharmaceutical Dosage Forms:Tablets, Vol. 1”, by H. Lieberman and L. Lachman, Marcel Dekker, N.Y.,N.Y., 1980 (ISBN 0-8247-6918-X).

Sol id formulations for oral administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted and programmedrelease

Parenteral Administration

The compounds of the invention may also be administered directly intothe blood stream, into muscle, or into an internal organ. Suitable meansfor parenteral administration include intravenous, intraarterial,intraperitoneal, intrathecal, intraventricular, intraurethral,intrasternal, intracranial, intramuscular and subcutaneous.

Suitable devices for parenteral administration includes needle(including microneedle) injectors, needle-free injectors and infusiontechniques. An example of a needle free injection is Powderject™.

Parenteral formulations are typically aqueous solutions which maycontain excipients such as salts, carbohy-drates and buffering agents(preferably, to a pH of from 3 to 9), but, for some applications, theymay be more suitably formulated as a sterile nonaqueous solution or as apowdered, dried form to be used in conjunction with a suitable vehiclesuch as sterile, pyrogen-free water.

The preparation of parenteral formulations under sterile conditions, forexample, by lyophilisation, may readily be accomplished using standardpharmaceutical techniques well known to those skilled in the art.

A proper dosage form such as combination with solubility enhancer canincrease solubility of compound of formula I used in non-oral solution.

Formulations for parenteral administration may be formulated to beimmediate and/or modified/controlled release. Controlled/modifiedrelease formulations include delayed-, sustained-, pulsed-, controlled-,targeted and programmed release. Thus compounds of the invent ion may beformulated as a solid, semi-solid, or thixotropic liquid foradministration as an implanted depot providing modified release of theactive compound. Examples of such formulations include drug-coatedstents and PGLA microspheres.

Local Administration

The compounds of the invention may also be administered topically to theskin or mucosa, that is, dermally or transdermally. Typical formulationsfor this purpose include gels, hydrogels, lotions, solutions, creams,ointments, dusting powders, dressings, foams, films, skin patches,wafers, implants, sponges, fibres, bandages and microemulsions.Li-posomes may also be used.

Does

In human patients, the precise daily dose administered depends onvarious factors such as the age, sex, weight and condition of thepatient being treated. The amount of dose can be selected within thebounds of goal achieving treatment effect without harmful or seriousadverse effect.

For instance, the dosage of the compound of invention may beadministered in an effective amount raging from 0.05 to 1000 mg daily onpatients. The following dosage levels and other dosage levels herein arefor the average human subject having a weight range of about 65 to 70kg. The skilled person will readily be able to determine the dosagelevels required for a subject whose weight falls outside this range,such as children and the elderly.

The present invention explain, but are not limited, in detail throughthe following examples and experimental examples.

EXAMPLE Example 1(R)-4-(3-(3-aminopyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-1) Step 1: Preparation of((R)-benzyl(1-(2-fluoro-5-formylbenzoyl)pyrrolidin-3-yl)carbamate

2-fluoro-5-formylbenzoic acid (220 mg, 0.91 mmol),O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU, 384 mg, 1.01 mmol) and N,N-diisopropyl ethylamine (DIPEA, 0.52mL, 2.98 mmol) was added to a solution of (R)-benzylpyrrolidin-3-ylcarbamate (200 mg, 0.91 mmol) in DMF (5 mL) and stirredfor 12 hours. The react ion mixture was concentrated in vacuum, addeddichloromethane and washed sat. NH₄Cl (ag) and water. The combinedorganic layers were dried over MgSO₄, filtered, evaporated in vacuum andpurified using silica chromatography to give the intermediate compound(R)-benzyl (1-(2-fluoro-5-formylbenzoyl)pyrrolidin-3-yl)carbamate (229mg, 68%).

Step 2: Preparation of(R,Z)-benzyl(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidin-3-yl)carbamate

The intermediate compound (Step 1)(236 mg, 0.62 mmol) and triethylamine(0.12 mL, 0.81 mmol) was added to a solution of dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (220 mg, 0.91 mmol) inTHF (1.7 mL) and stirred for 5 hours at 0° C. The reaction mixture wasconcentrated in vacuum then the white residue was slurried in water for30 minutes, filtered, washed with water, hexane and ether, and dried toyield the intermediate compound (R,Z)-benzyl(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidin-3-yl)carbamate(164 mg, 59%).

Step 3: Preparation of(R)-benzyl(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)carbamate

Hydrazine monohydrate (19 uL, 0.38 mmol) was added to a suspension ofthe intermediate compound (Step 2)(164 mg, 0.35 mmol) in water (1.5 mL)and stirred for 2 hours at 40° C. The reaction was cooled to roomtemperature and concentrated in vacuum. Water was added to the react ionmixture and the product was extracted into dichloromethane. The combinedorganic layers were dried over MgSO₄, filtered, evaporated in vacuum andpurified using silica chromatography to give(R)-benzyl(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)carbamate(100 mg, 47%).

Step 4: Preparation of(R)-4-(3-(3-aminopyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

The intermediate compound (step 3)(100 mg, 0.20 mmol) and 10 wt. % Pd/C(10 mg) in methanol (30 mL) was hydrogenated at atmosphere for 6 h. Thereaction mixture was filtered, evaporated in vacuum and purified usingsilica chromatography to afford the title compound (63 mg, 85%).

¹H-NMR (DMSO, 400 MHz): δ 12.60 (s, 1H), 8.26 (d, 1H), 7.97 (d, 1H),7.89 (t, 1H), 7.83 (t, 1H), 7.50-7.44 (m, 1H), 7.40 (d, 1H), 7.21 (t,1H), 4.37 (s, 2H), 3.79-3.67 (m, 1H), 3.59-3.33 (m, 3H), 3.29-3.06 (m,3H).

Example 2(S)-4-(3-(3-aminopyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-2) Step 1: Preparation of(S)-benzyl(1-(2-fluoro-5-formylbenzoyl)pyrrolidin-3-yl)carbamate

This compound was made using the procedure described for example 1 (Step1). Thus, (S)-benzylpyrrolidine-3-ylcarbamate (150 mg, 0.68 mmol) wasreacted with 2-fluoro-5-formyl benzoic acid (114 mg, 0.68 mmol),O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU, 335 mg, 0.88 mmol) and N,N-diisopropyl ethyl amine (DIPEA, 0.24mL, 1.36 mmol) to afford the intermediate compound (S)-benzyl(1-(2-fluoro-5-formylbenzoyl)pyrrolidin-3-yl)carbamate (156 mg, 62%).

Step 2: Preparation of(S,Z)-benzyl(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidin-3-yl)carbamate

This compound was made using the procedure described for example 1 (Step2). Thus, this intermediate compound (Step 1) was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (102 mg, 0.42 mmol) andtriethyl amine (88 uL, 0.63 mmol) to afford the intermediate compound(S,Z)-benzyl(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidin-3-yl)carbamate(117 mg, 57%).

Step 3: Preparation of(S)-benzyl(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)carbamate

This compound was made using the procedure described for example 1 (Step3). Thus, this intermediate compound (Step 2) was reacted with hydrazinemonohydrate (24 uL, 0.48 mmol) to afford the intermediate compound(S)-benzyl (1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)carbamate (58 mg, 48%).

Step 4: Preparation of(S)-4-(3-(3-aminopyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 1 (Step4). Thus, this intermediate compound (Step 3)(58 mg, 0.12 mmol) wasreacted with 10 wt. Pd/C (6 mg) to afford the title compound (39 mg,88%).

¹H-NMR (DMSO, 400 MHz): δ 12.60 (s, 1H), 8.26 (d, 1H), 7.97 (d, 1H),7.89 (t, 1H), 7.83 (t, 1H), 7.50-7.44 (m, 1H), 7.40 (d, 1H), 7.21 (t,1H), 4.37 (s, 2H), 3.79-3.67 (m, 1H), 3.59-3.33 (m, 3H), 3.29-3.06 (m,3H).

Example 34-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-3) Step 1: Preparation ofbenzyl(1-(2-fluoro-5-formylbenzoyl)azetidin-3-yl)carbamate

This compound was made using the procedure described for example 1 (Step1). Thus, benzyl azetidine-3-ylcarbamate (500 mg, 2.42 mmol) was reactedwith 2-fluoro-5-formyl benzoic acid (408 mg, 2.42 mmol),O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU, 1.20 g, 3.15 mmol) and N,N-diisopropyl ethylamine (DIPEA, 0.84mL, 4.85 mmol) to affoed the intermediate compound benzyl(1-(2-fluoro-5-formylbenzoyl)azetidin-3-yl)carbamate (604 mg, 70%).

Step 2: Preparation of(Z)-benzyl(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)azetidin-3-yl)carbamate

This compound was made using the procedure described for example 1 (Step2). Thus, this intermediate compound (Step 1)(604 mg, 1.69 mmol) wasreacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate(410 mg, 1.69 mmol) and triethylamine (0.35 mL, 2.54 mmol) to afford theintermediate compound (Z)-benzyl(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)azetidin-3-yl)carbamate(497 mg, 62%).

Step 3: Preparation ofbenzyl(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)carbamate

This compound was made using the procedure described for example 1 (Step3). Thus, this intermediate compound (Step 2)(497 mg, 1.05 mmol) wasreacted with hydrazine monohydrate (0.1 mL, 2.1 mmol) to afford theintermediate compound benzyl(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)carbamate(261 mg, 51%).

Step 4: Preparation of4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 1 (Step4). Thus, this intermediate compound (Step 3)(261 mg, 0.54 mmol) wasreacted with 10 wt. % Pd/C (30 mg) to afford the title compound (174 mg,91%).

¹H-NMR (DMSO, 400 MHz): δ 12.61 (s, 1H), 8.27-8.25 (m, 1H), 7.97 (d,1H), 7.91-7.81 (m, 2H), 7.48-7.44 (m, 1H), 7.41-7.39 (m, 1H), 7.21 (t,1H), 4.33 (s, 2H), 4.15-4.10 (m, 2H), 3.66-3.59 (m, 3H).

Example 4(R)-4-(4-fluoro-3-(3-hydroxypyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-4) Step 1: Preparation of(R)-3-(3-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde

This compound was made using the procedure described for example 1 (Step1). Thus, (R)-3-((tert-butyldimethylsilyl)oxy)pyrrolidine (300 mg, 1.49mmol) was reacted with 2-fluoro-5-formyl benzoic acid (250 mg, 1.49mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU, 734 mg, 1.93 mmol) and N,N-diisopropylethylamine (DIPEA, 0.52 mL, 2.97 mmol) to afford the intermediatecompound(R)-3-(3-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde(377 mg, 72%).

Step 2: Preparation of(R,Z)-3-(3-(3-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one

This compound was made using the procedure described for example 1 (Step2). Thus, this intermediate compound (Step 1)(377 mg, 1.07 mmol) wasreacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate(260 mg, 1.07 mmol) and trietylamine (0.22 mL, 1.61 mmol) to afford theintermediate compound(R,Z)-3-(3-(3-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carbonyl)-4-fluorobenzyidene)isobenzofuran-1(3H)-one(300 mg, 60%).

Step 3: Preparation of((R)-4-(3-(3-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 1 (Step3). Thus, this intermediate compound (Step 2)(300 mg, 0.64 mmol) wasreacted with hydrazine monohydrate (63 uL, 1.28 mmol) to afford theintermediate compound(R)-4-(3-(3-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(148 mg, 48%).

Step 4: Preparation of(R)-4-(4-fluoro-3-(3-hydroxypyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

The intermediate compound (step 3)(148 mg, 0.30 mmol) in THF (3 mL)cooled to 0° C. was added 1M solution of tetra-n-butylammonium fluoridein THF (TBAF, 0.60 mL, 0.60 mmol), and the mixture was stirred at roomtemperature for 3 h. The reaction mixture was concentrated in vacuum,added dichloromethane and washed with sat. NH₄Cl (ag) and water. Thecombined organic layers were dried over MgSO₄, filtered, evaporated invacuum and purified using silica chromatography to afford the titlecompound (101 mg, 92%).

¹H-NMR (DMSO, 400 MHz): δ 12.61 (s, 1H), 8.25 (d, 1H), 7.98 (d, 1H),7.87 (t, 1H), 7.82 (t, 1H), 7.51-7.45 (m, 1H), 7.40 (d, 1H), 7.21 (t,1H), 4.37 (s, 2H), 3.79-3.65 (m, 2H), 3.59-3.28 (m, 5H).

Example 5(S)-4-(4-fluoro-3-(3-hydroxypyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-oneStep 1: Preparation of(S)-3-(3-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde

This compound was made using the procedure described for example 1 (Step1). Thus, (S)-3-((tert-butyldimethylsilyl)oxy)pyrrolidine (300 mg, 1.49mmol) was reacted with 2-fluoro-5-formyl benzoic acid (250 mg, 1.49mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU, 734 mg, 1.93 mmol) and N,N-diisopropylethylamine (DIPEA, 0.52 mL, 2.97 mmol) to afford the intermediatecompound(S)-3-(3-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde(377 mg, 72%).

Step 2: Preparation of(S,Z)-3-(3-(3-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one

This compound was made using the procedure described for example 1 (Step2). Thus, this intermediate compound (Step 1)(377 mg, 1.07 mmol) wasreacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate(260 mg, 1.07 mmol) and trietylamine (0.22 mL, 1.61 mmol) to afford theintermediate compound(S,Z)-3-(3-(3-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one(300 mg, 60%).

Step 3: Preparation of(S)-4-(3-(3-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 1 (Step3). Thus, this intermediate compound (Step 2)(300 mg, 0.64 mmol) wasreacted with hydrazine monohydrate (63 uL, 1.28 mmol) to afford theintermediate compound(S)-4-(3-(3-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(148 mg, 48%).

Step 4: Preparation of(S)-4-(4-fluoro-3-(3-hydroxypyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 4 (Step4). Thus, this intermediate compound (Step 3)(144 mg, 0.30 mmol) wasreacted with a 1M solution of tetra-n-butylammonium fluoride in THF(TBAF, 0.60 mL, 0.60 mmol) to afford the title compound (101 mg, 92%).

¹H-NMR (DMSO, 400 MHz): δ 12.61 (s, 1H), 8.25 (d, 1H), 7.98 (d, 1H),7.87 (t, 1H), 7.82 (t, 1H), 7.51-7.45 (m, 1H), 7.40 (d, 1H), 7.21 (t,1H), 4.37 (s, 2H), 3.79-3.65 (m, 2H), 3.59-3.28 (m, 5H).

Example 64-(4-fluoro-3-(3-hydroxyazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-6) Step 1: Preparation of3-(3-((tert-butyldimethylsilyl)oxy)azetidine-1-carbonyl)-4-fluorobenzaldehyde

This compound was made using the procedure described for example 1 (Step1). Thus, 3-((tert-butyldimethylsilyl)oxy)azetidine (300 mg, 1.60 mmol)was reacted with 2-fluoro-5-formyl benzoic acid (269 mg, 1.60 mmol),O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU, 789 mg, 2.08 mmol) and N,N-diisopropyl ethylamine (DIPEA, 0.56mL, 3.20 mmol) to afford the intermediate compound3-(3-((tert-butyldimethylsilyl)oxy)azetidine-1-carbonyl)-4-fluorobenzaldehyde(378 mg, 70%).

Step 2: Preparation of(Z)-3-(3-(3-((tert-butyldimethylsilyl)oxy)azetidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one

This compound was made using the procedure described for example 1 (Step2). Thus, this intermediate compound (Step 1)(378 mg, 1.12 mmol) wasreacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate(271 mg, 1.12 mmol) and trietylamine (0.23 mL, 1.68 mmol) to afford theintermediate compound(Z)-3-(3-(3-((tert-butyldimethylsilyl)oxy)azetidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one(284 mg, 56%).

Step 3: Preparation of4-(3-(3-((tert-butyldimethylsilyl)oxy)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 1 (Step3). Thus, this intermediate compound (Step 2)(284 mg, 0.62 mmol) wasreacted with hydrazine monohydrate (61 uL, 1.26 mmol) to afford theintermediate compound4-(3-(3-((tert-butyldimethylsilyl)oxy)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(149 mg, 51%).

Step 4: Preparation of4-(4-fluoro-3-(3-hydroxyazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 4 (Step4). Thus, this intermediate compound (Step 3)(149 mg, 0.32 mmol) wasreacted with a 1M solution of tetra-n-butylammonium fluoride in THF(TBAF, 0.64 mL, 0.64 mmol) to afford the title compound (98 mg, 92%).

¹H-NMR (DMSO, 400 MHz): δ 12.60 (s, 1H), 8.27-8.26 (m, 1H), 7.96 (d,1H), 7.91-7.81 (m, 2H), 7.48-7.45 (m, 1H), 7.41-7.39 (m, 1H), 7.20 (t,1H), 4.33 (s, 2H), 4.15-4.11 (m, 3H), 3.66-3.58 (m, 2H).

Example 74-(4-fluoro-3-(3-(hydroxyethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-7) Step 1: Preparation of3-(3-(((tert-butyldimethylsilyl)oxy)methyl)azetidine-1-carbonyl)-4-fluorobenzaldehyde

This compound was made using the procedure described for example 1 (Step1). Thus, 3-(((tert-butyldimethylsilyl)oxy)methyl)azetidine (300 mg,1.60 mmol) was reacted with 2-fluoro-5-formyl benzoic acid (269 mg, 1.60mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU, 789 mg, 2.08 mmol) and N,N-diisopropylethylamine (DIPEA, 0.56 mL, 3.20 mmol) to afford the intermediatecompound3-(3-(((tert-butyldimethylsilyl)oxy)methyl)azetidine-1-carbonyl)-4-fluorobenzaldehyde(378 mg, 72%).

Step 2: Preparation of(Z)-3-(3-(3-(((tert-butyldimethylsilyl)oxy)methyl)azetidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one

This compound was made using the procedure described for example 1 (Step2). Thus, this intermediate compound (Step 1)(378 mg, 1.12 mmol) wasreacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate(271 mg, 1.12 mmol) and trietylamine (0.23 mL, 1.68 mmol) to afford theintermediate compound(Z)-3-(3-(3-(((tert-butyldimethylsilyl)oxy)methyl)azetidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one(284 mg, 56%).

Step 3: Preparation of4-(3-(3-(((tert-butyldimethylsilyl)oxy)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 1 (Step3). Thus, this intermediate compound (Step 2)(284 mg, 0.63 mmol) wasreacted with hydrazine monohydrate (61 uL, 1.25 mmol) to afford theintermediate compound4-(3-(3-(((tert-butyldimethylsilyl)oxy)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(149 mg, 51%).

Step 4: Preparation of4-(4-fluoro-3-(3-(hydroxymethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 4 (Step4). Thus, this intermediate compound (Step 3)(149 mg, 0.32 mmol) wasreacted with a 1M solution of tetra-n-butylammonium fluoride in THF(TBAF, 0.64 mL, 0.64 mmol) to afford the title compound (98 mg, 92%).

¹H-NMR (DMSO, 400 MHz): δ 12.61 (s, 1H), 8.28-8.26 (m, 1H), 7.97 (d,1H), 7.92-7.81 (m, 2H), 7.49-7.45 (m, 1H), 7.42-7.39 (m, 1H), 7.21 (t,1H), 4.33 (s, 2H), 4.15-4.11 (m, 3H), 3.66-3.58 (m, 2H), 3.47 (m, 2H).

Example 8(R)—N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)cyclopropanecarboxamide;(I-8) Step 1: Preparation of(R)—N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)cyclopropanecarboxamide

Cyclopropanecarboxylic acid (20 uL, 0.28 mmol),1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 66mg, 0.42 mmol) and 4-(Dimethylamino)pyridine (DMAP, 68 mg, 0.56 mmol)was added to a solution of(R)-4-(3-(3-aminopyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 1)(100 mg, 0.28 mmol) in dichloromethane (1.5 mL) and stirredfor 12 hours. The reaction mixture was concentrated in vacuum, addeddichloromethane and washed sat. NH₄Cl (ag) and water. The combinedorganic layers were dried over MgSO₄, filtered, evaporated in vacuum andpurified using silica chromatography to afford title compound (83 mg,68%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.36 (d, 1H), 8.46 (m, 1H), 7.79 (m, 2H),7.71 (m, 1H), 7.35 (m, 1H), 7.32 (m, 1H), 7.04 (q, 1H), 5.89 (m, 1H),4.60 (q, 0.3H), 4.45 (q, 0.7H), 4.26 (d, 2H), 3.82 (m, 1H), 3.65 (m,1H), 3.51 (m, 1H), 3.40 (m, 1H), 3.18 (m, 1H), 2.28 (m, 2H), 1.61 (m,1H), 0.98 (m, 11H), 0.96 (m, 2H), 0.74 (m, 2H).

Example 9N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)cyclopropanecarboxamide;(I-9) Step 1: Preparation ofN-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)cyclopropanecarboxamide

This compound was made using the procedure described for example 8 (Step1). Thus,4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(100 mg, 0.28 mmol) was reacted with cyclopropanecarboxylicacid (20 uL, 0.28 mmol), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (EDCI, 66 mg, 0.42 mmol) and 4-(Dimethylamino)pyridine(DMAP, 68 mg, 0.56 mmol) to afford the title compound (78 mg, 62%).

¹H-NMR (MeOD, 400 MHz): δ 8.39 (dd, 1H), 7.94 (dd, 1H), 7.85-7.80 (m,2H), 7.52-7.45 (m, 2H), 7.17-7.12 (m, 1H), 4.63-4.53 (m, 1H), 4.44-4.37(m, 3H), 4.30-4.21 (m, 1H), 4.01-3.89 (m, 2H), 1.59-1.52 (m, 1H),0.92-0.78 (m, 4H).

Example 10(S)—N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)cyclopropanecarboxamide;(I-10) Step 1: Preparation of(S)—N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)cyclopropanecarboxamide

This compound was made using the procedure described for example 8 (Step1). Thus,(S)-4-(3-(3-aminopyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 2)(100 mg, 0.28 mmol) was reacted with cyclopropanecarboxylicacid (20 uL, 0.28 mmol), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (EDCI, 66 mg, 0.42 mmol) and 4-(Dimethylamino)pyridine(DMAP, 68 mg, 0.56 mmol) to afford the title compound (77 mg, 65%).

¹H-NMR (CDCl₃, 400 MHz): δ 9.55 (s, 0.6H), 9.52 (s, 0.6H), 8.46 (d, 1H),7.82-7.71 (m, 3H), 7.38-7.26 (m, 2H), 7.04 (q, 1H), 5.75 (m, 1H), 4.60(m, 0.4H), 4.42 (m, 0.6H), 4.28 (s, 0.8H), 4.27 (s, 1.2H), 3.92-3.64 (m,2.4H), 3.56-3.33 (m, 1H), 3.17 (dd, 0.6H), 2.33-2.16 (m, 1H), 1.93 (m,1H), 1.32 (m, 1H), 0.96 (m, 2H), 0.75 (m, 2H).

Example 11(R)—N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)-N-methylcyclopropanecarboxamide;(I-11) Step 1: Preparation of(R)—N-(1-(2-fluoro-5-formylbenzoyl)pyrrolidin-3-yl)-N-methylcyclopropanecarboxamide

2-fluoro-5-formylbenzoic acid (350 mg, 2.08 mmol),O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU, 1.02 g, 2.79 mmol) and N,N-diisopropyl ethylamine (DIPEA, 0.72mL, 4.16 mmol) was added to a solution of(R)—N-methyl-N-(pyrrolidin-3-yl)cyclopropanecarboxamide (350 mg, 2.08mmol) in DMF (5 mL) and stirred for 12 hours. The react ion mixture wasconcentrated in vacuum, added dichloromethane and washed sat. NH₄Cl (ag)and water. The combined organic layers were dried over MgSO₄, filtered,evaporated in vacuum and purified using silica chromatography to affordthe intermediate compound(R)—N-(1-(2-fluoro-5-formylbenzoyl)pyrrolidin-3-yl)-N-methylcyclopropanecarboxamide(470 mg, 72%).(R)-benzyl(1-(2-fluoro-5-formylbenzoyl)pyrrolidin-3-yl)carbamate (229mg, 68%).

Step 2: Preparation of(R,Z)—N-(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidin-3-yl)-N-methylcyclopropanecarboxamide

Trietylamine (0.38 mL, 2.21 mmol) was added drop-wide to a solution ofthe intermediate compound (Step 1)(470 mg, 1.48 mmol) and dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (357 mg, 1.48 mmol) inTHF (1.7 mL) and stirred for 5 hours at 0° C. The reaction mixture wasconcentrated in vacuum then the white residue was slurried in water for30 minutes, filtered, washed with water, hexane and ether, and dried toafford the intermediate compound(R,Z)—N-(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidin-3-yl)-N-methylcyclopropanecarboxamide(398 mg, 62%).

Step 3: Preparation of(R)—N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)-N-methylcyclopropanecarboxamide

Hydrazine monohydrate (90 uL, 1.83 mmol) was added to a suspension ofthe intermediate compound (Step 2)(398 mg, 0.92 mmol) in ethanol (1.5mL) and stirred at 40° C. for 2 hours. The reaction was cooled to roomtemperature and concentrated in vacuum. Water was added to the react ionmixture and the product was extracted into dichloromethane. The combinedorganic layers were dried over MgSO₄, filtered, evaporated in vacuum andpurified using silica chromatography to afford the title compound (184mg, 45%).

¹H-NMR (CDCl₃, 400 MHz): δ 5.35 (q, 0.7H), 4.78 (q, 0.3H), 3.65 (m, 1H),3.51 (m, 1H), 3.40 (m, 1H), 3.01 (s, 3H), 2.28 (m, 2H), 1.61 (m, 1H),0.98 (m, 1H), 0.96 (m, 2H), 0.74 (m, 2H).

Example 12N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)ethyl)benzoyl)azetidin-3-yl)-N-ethylcyclopropanecarboxamide;(I-12) Step 1: Preparation ofN-(1-(2-fluoro-5-formylbenzoyl)azetidin-3-yl)-N-methylcyclopropanecarboxamide

This compound was made using the procedure described for example 11(Step 1). Thus, N-(azetidin-3-yl)-N-methylcyclopropanecarboxamide (200mg, 1.30 mmol) was reacted with 2-fluoro-5-formyl benzoic acid (218 mg,1.30 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU, 640 mg, 1.68 mmol) and N,N-diisopropylethylamine (DIPEA, 0.45 mL, 2.59 mmol) to afford the intermediatecompoundN-(1-(2-fluoro-5-formylbenzoyl)azetidin-3-yl)-N-methylcyclopropanecarboxamide(256 mg, 65%).

Step 2: Preparation of(Z)—N-(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)azetidin-3-yl)-N-methylcyclopropanecarboxamide

This compound was made using the procedure described for example 11(Step 2). Thus, this intermediate compound (Step 1)(256 mg, 0.84 mmol)was reacted withdimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (204 mg, 0.84mmol) and trietylamine (0.17 mL, 1.26 mmol) to afford the intermediatecompound(Z)—N-(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)azetidin-3-yl)-N-methylcyclopropanecarboxamide(202 mg, 57%).

Step 3: Preparation ofN-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)-N-methylcyclopropanecarboxamide

This compound was made using the procedure described for example 11(Step 3). Thus, this intermediate compound (Step 2)(202 mg, 0.48 mmol)was reacted with hydrazine monohydrate (46 uL, 0.96 mmol) to afford thetitle compound (106 mg, 51%).

¹H-NMR (MeOD, 400 MHz): δ 8.39 (dd, 1H), 7.94 (dd, 1H), 7.85-7.80 (m,2H), 7.52-7.45 (m, 2H), 7.17-7.12 (m, 1H), 4.63-4.53 (m, 1H), 4.44-4.37(m, 3H), 4.30-4.21 (m, 1H), 4.01-3.89 (m, 2H), 3.26 (s, 3H), 1.59-1.52(m, 1H), 0.92-0.78 (m, 4H).

Example 13(S)—N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)ethyl)benzoyl)pyrrolidin-3-yl)-N-methylcyclopropanecarboxamide;(I-13) Step 1: Preparation of(S)—N-(1-(2-fluoro-5-formylbenzoyl)pyrrolidin-3-yl)-N-methylcyclopropanecarboxamide

This compound was made using the procedure described for example 11(Step 1). Thus, (S)—N-methyl-N-(pyrrolidin-3-yl)cyclopropanecarboxamide(350 mg, 2.08 mmol) was reacted with 2-fluoro-5-formyl benzoic acid (349mg, 2.08 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU, 1.02 mg, 2.70 mmol) and N,N-diisopropylethylamine (DIPEA, 0.72 mL, 4.16 mmol) to afford the intermediatecompound(S)—N-(1-(2-fluoro-5-formylbenzoyl)pyrrolidin-3-yl)-N-methylcyclopropanecarboxamide(470 mg, 71%).

Step 2: Preparation of(S,Z)—N-(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidin-3-yl)-N-methylcyclopropanecarboxamide

This compound was made using the procedure described for example 11(Step 2). Thus, this intermediate compound (Step 1)(470 mg, 1.48 mmol)was reacted withdimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (357 mg, 1.48mmol) and trietylamine (0.31 mL, 2.12 mmol) to afford the intermediatecompound(S,Z)—N-(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidin-3-yl)-N-methylcyclopropanecarboxamide(397 mg, 62%).

Step 3: Preparation of(S)—N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)-N-methylcyclopropanecarboxamide

This compound was made using the procedure described for example 11(Step 3). Thus, this intermediate compound (Step 2)(397 mg, 0.92 mmol)was reacted with hydrazine monohydrate (90 uL, 1.83 mmol) to afford thetitle compound (185 mg, 45%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.13 (s, 0.5H), 9.97 (s, 0.5H), 8.46 (s,1H), 7.81-7.70 (m, 3H), 7.37 (m, 1H), 7.30 (m, 1H), 7.03 (q, 1H), 5.34(m, 0.5H), 5.13 (m, 0.5H), 4.27 (d, 2H), 3.88 (m, 0.5H), 3.78 (m, 0.5H),3.66-3.34 (m, 3H), 3.20-3.14 (m, 3.5H), 2.98-2.82 (m, 0.5H), 2.20-2.06(m, 1H), 1.78-1.65 (m, 1H), 1.06-0.92 (m, 2H), 0.81 (m, 2H).

Example 143-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)ethyl)benzoyl)azetidin-3-yl)-5,5-dimethylimidazolidine-2,4-dione;(I-14) Step 1: Preparation of3-(3-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)azetidine-1-carbonyl)-4-fluorobenzaldehyde

This compound was made using the procedure described for example 11(Step 1). Thus, 3-(azetidin-3-yl)-5,5-dimethylimidazolidine-2,4-dione(150 mg, 0.82 mmol) was reacted with 2-fluoro-5-formyl benzoic acid (137mg, 0.82 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU, 403 mg, 1.06 mmol) and N,N-diisopropylethylamine (DIPEA, 0.29 mL, 1.63 mmol) to afford the intermediatecompound3-(3-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)azetidine-1-carbonyl)-4-fluorobenzaldehyde(152 mg, 56%).

Step 2: Preparation of(Z)-3-(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)azetidin-3-yl)-5,5-dimethylimidazolidine-2,4-dione

This compound was made using the procedure described for example 11(Step 2). Thus, this intermediate compound (Step 1)(152 mg, 0.45 mmol)was reacted withdimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (111 mg, 0.45mmol) and trietylamine (96 uL, 0.68 mmol) to afford the intermediatecompound(Z)-3-(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)azetidin-3-yl)-5,5-dimethylimidazolidine-2,4-dione(89 mg, 43%).

Step 3: Preparation of3-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)-5,5-dimethylimidazolidine-2,4-dione

This compound was made using the procedure described for example 11(Step 3). Thus, this intermediate compound (Step 2)(89 mg, 0.19 mmol)was reacted with hydrazine monohydrate (20 uL, 0.39 mmol) to afford thetitle compound (47 mg, 51%).

¹H-NMR (MeOD, 400 MHz): δ 8.36-8.35 (m, 1H), 7.92 (t, 1H), 7.98 (d, 1H),7.90-7.82 (m, 2H), 7.48-7.43 (m, 2H), 7.22 (t, 1H), 4.34 (s, 2H),4.07-4.03 (m, 1H), 3.94 (t, 1H), 3.85-3.76 (m, 2H), 3.27-3.23 (m, 1H),1.32 (s, 6H).

Example 15(R)-3-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)ethyl)benzoyl)pyrrolidin-3-yl)imidazolidine-2,4-dione;(I-15) Step 1: Preparation of(R)-3-(3-(2,5-dioxoimidazolidin-1-yl)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde

This compound was made using the procedure described for example 11(Step 1). Thus, (R)-3-(pyrrolidin-3-yl)imidazolidine-2,4-dione (150 mg,0.88 mmol) was reacted with 2-fluoro-5-formyl benzoic acid (149 mg, 0.88mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU, 437 mg, 1.15 mmol) and N,N-diisopropylethylamine (DIPEA, 0.31 mL, 1.77 mmol) to afford the intermediatecompound(R)-3-(3-(2,5-dioxoimidazolidin-1-yl)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde(158 mg, 56%).

Step 2: Preparation of(R,Z)-3-(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidin-3-yl)imidazolidine-2,4-dione

This compound was made using the procedure described for example 11(Step 2). Thus, this intermediate compound (Step 1)(158 mg, 0.50 mmol)was reacted withdimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (120 mg, 0.50mmol) and trietylamine (58 uL, 0.42 mmol) to afford the intermediatecompound(R,Z)-3-(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidin-3-yl)imidazolidine-2,4-dione(93 mg, 43%).

Step 3: Preparation of(R)-3-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)imidazolidine-2,4-dione

This compound was made using the procedure described for example 11(Step 3). Thus, this intermediate compound (Step 2)(93 mg, 0.21 mmol)was reacted with hydrazine monohydrate (21 uL, 0.43 mmol) to afford thetitle compound (54 mg, 56%).

¹H-NMR (MeOD, 400 MHz): δ 8.35-8.32 (m, 1H), 7.91 (t, 1H), 7.86-7.77 (m,2H), 7.47-7.38 (m, 2H), 7.16-7.10 (m, 1H), 4.80-4.58 (m, 1H), 4.35 (d,2H), 3.98-3.94 (m, 2H), 3.68-3.60 (m, 1H), 3.51-3.45 (m, 2H), 2.50-2.32(m, 1H), 2.24-2.12 (m, 2H).

Example 16(R)-1-ethyl-3-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)imidazolidine-2,4-dione;(I-16) Step 1: Preparation of(R)-3-(3-(3-ethyl-2,5-dioxoimidazolidin-1-yl)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde

This compound was made using the procedure described for example 11(Step 1). Thus, (R)-1-ethyl-3-(pyrrolidin-3-yl)imidazolidine-2,4-dione(200 mg, 1.01 mmol) was reacted with 2-fluoro-5-formyl benzoic acid (170mg, 1.01 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU, 500 mg, 1.31 mmol) and N,N-diisopropylethylamine (DIPEA, 0.35 mL, 2.02 mmol) to afford the intermediatecompound(R)-3-(3-(3-ethyl-2,5-dioxoimidazolidin-1-yl)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde(197 mg, 56%).

Step 2: Preparation of(R,Z)-1-ethyl-3-(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidin-3-yl)imidazolidine-2,4-dione

This compound was made using the procedure described for example 11(Step 2). Thus, this intermediate compound (Step 1)(197 mg, 0.56 mmol)was reacted withdimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (137 mg, 0.56mmol) and trietylamine (0.12 mL, 0.85 mmol) to afford the intermediatecompound(R,Z)-1-ethyl-3-(1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidin-3-yl)imidazolidine-2,4-dione(134 mg, 51%).

Step 3: Preparation of(R)-1-ethyl-3-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)imidazolidine-2,4-dione

This compound was made using the procedure described for example 11(Step 3). Thus, this intermediate compound (Step 2)(134 mg, 0.29 mmol)was reacted with hydrazine monohydrate (28 uL, 0.58 mmol) to afford thetitle compound (66 mg, 48%).

¹H-NMR (MeOD, 400 MHz): δ 8.37-8.34 (m, 1H), 7.92 (t, 1H), 7.87-7.80 (m,2H), 7.49-7.43 (m, 1H), 7.41-7.39 (m, 1H), 7.17-7.11 (m, 1H), 4.78-4.59(m, 1H), 4.37 (d, 2H), 3.94 (s, 2H), 3.87 (d, 2H), 3.84-3.79 (m, 1H),3.67-3.60 (m, 1H), 3.47-3.35 (m, 2H), 2.59-2.44 (m, 1H), 2.19 (d, 2H),1.20-1.13 (m, 3H).

Example 174-(4-fluoro-3-(3-(4-fluoropiperidine-1-carbonyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-17) Step 1: Preparation of4-fluoro-3-(3-(4-fluoropiperidine-1-carbonyl)azetidine-1-carbonyl)benzaldehyde

This compound was made using the procedure described for example 11(Step 1). Thus, azetidin-3-yl(4-fluoropiperidin-1-yl)methanone (200 mg,1.07 mmol) was reacted with 2-fluoro-5-formyl benzoic acid (180 mg, 1.07mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU, 529 mg, 1.40 mmol) and N,N-diisopropylethylamine (DIPEA, 0.37 mL, 2.14 mmol) to afford the intermediatecompound4-fluoro-3-(3-(4-fluoropiperidine-1-carbonyl)azetidine-1-carbonyl)benzaldehyde(216 mg, 60%).

Step 2: Preparation of(Z)-3-(4-fluoro-3-(3-(4-fluoropiperidine-1-carbonyl)azetidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one

This compound was made using the procedure described for example 11(Step 2). Thus, this intermediate compound (Step 1)(261 mg, 0.64 mmol)was reacted withdimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (156 mg, 0.64mmol) and trietylamine (0.13 mL, 0.96 mmol) to afford the intermediatecompound(Z)-3-(4-fluoro-3-(3-(4-fluoropiperidine-1-carbonyl)azetidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one(140 mg, 48%).

Step 3: Preparation of4-(4-fluoro-3-(3-(4-fluoropiperidine-1-carbonyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 11(Step 3). Thus, this intermediate compound (Step 2)(140 mg, 0.31 mmol)was reacted with hydrazine monohydrate (30 uL, 0.62 mmol) to afford thetitle compound (76 mg, 53%).

¹H-NMR (MeOD, 400 MHz): δ 8.36 (d, 1H), 7.95 (d, 1H), 7.79-7.90 (m, 2H),7.45-7.60 (m, 2H), 7.15 (t, 1H), 4.37 (s, 2H), 4.32 (d, 1H), 4.15-4.27(m, 3H), 3.70-3.88 (m, 2H), 3.41-3.62 (m, 2H), 3.27-3.36 (m, 2H),1.76-1.94 (m, 4H).

Example 184-(3-(3-(3,3-difluoroazetidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-18) Step 1: Preparation of3-(3-(3,3-difluoroazetidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzaldehyde

This compound was made using the procedure described for example 11(Step 1). Thus, azetidin-3-yl(3,3-difluoroazetidin-1-yl)methanone (200mg, 1.14 mmol) was reacted with 2-fluoro-5-formyl benzoic acid (190 mg,1.14 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU, 560 mg, 1.47 mmol) and N,N-diisopropylethylamine (DIPEA, 0.41 mL, 2.27 mmol) to afford the intermediatecompound3-(3-(3,3-difluoroazetidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzaldehyde(222 mg, 60%).

Step 2: Preparation of(Z)-3-(3-(3-(3,3-difluoroazetidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one

This compound was made using the procedure described for example 11(Step 2). Thus, this intermediate compound (Step 1)(222 mg, 0.68 mmol)was reacted withdimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (164 mg, 0.68mmol) and trietylamine (0.14 mL, 1.02 mmol) to afford the intermediate(Z)-3-(3-(3-(3,3-difluoroazetidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one(145 mg, 48%).

Step 3: Preparation of4-(3-(3-(3,3-difluoroazetidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 11(Step 3). Thus, this intermediate compound (Step 2)(145 mg, 0.33 mmol)was reacted with hydrazine monohydrate (31 uL, 0.65 mmol) to afford thetitle compound (79 mg, 53%).

¹H-NMR (MeOD, 400 MHz): δ 8.36 (d, 1H), 7.94 (d, 1H), 7.79-7.89 (m, 2H),7.46-7.58 (m, 2H), 7.14 (t, 1H), 4.46-4.64 (m, 2H), 4.25-4.40 (m, 5H),4.05-4.23 (m, 3H), 3.51-3.59 (m, 1H).

Example 194-(3-(3-(3,3-difluoropyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-19) Step 1: Preparation of3-(3-(3,3-difluoropyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzaldehyde

This compound was made using the procedure described for example 11(Step 1). Thus, azetidin-3-yl(3,3-difluoropyrrolidin-1-yl)methanone (200mg, 1.05 mmol) was reacted with 2-fluoro-5-formyl benzoic acid (176 mg,1.05 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU, 518 mg, 1.05 mmol) and N,N-diisopropylethylamine (DIPEA, 0.37 mL, 1.37 mmol) to afford the intermediatecompound3-(3-(3,3-difluoropyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzaldehyde(214 mg, 60%).

Step 2: Preparation of(Z)-3-(3-(3-(3,3-difluoropyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one

This compound was made using the procedure described for example 11(Step 2). Thus, this intermediate compound (Step 1)(214 mg, 0.63 mmol)was reacted withdimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (152 mg, 0.63mmol) and trietylamine (0.13 mL, 0.94 mmol) to afford the intermediatecompound(Z)-3-(3-(3-(3,3-difluoropyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one(138 mg, 48%).

Step 3: Preparation of4-(3-(3-(3,3-difluoropyrrolidine-1-carbonyl-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 11(Step 3). Thus, this intermediate compound (Step 2)(138 mg, 0.31 mmol)was reacted with hydrazine monohydrate (30 uL, 0.62 mmol) to afford thetitle compound (75 mg, 53%).

¹H-NMR (MeOD, 400 MHz): δ 8.36 (d, 1H), 7.95 (d, 1 Hz), 7.80-7.90 (m,2H), 7.45-7.54 (m, 2H), 7.15 (t, 1H), 4.38 (s, 2H), 4.29-4.36 (m, 2H),4.16-4.28 (m, 3H), 3.58-3.85 (m, 4H), 2.36-2.51 (m, 2H).

Example 204-(3-(3-(3,3-difluoropyrrolidine-1-carbonyl)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-20) Step 1: Preparation of3-(3-(3,3-difluoropyrrolidine-1-carbonyl)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde

This compound was made using the procedure described for example 11(Step 1). Thus, (3,3-difluoropyrrolidin-1-yl)(pyrrolidin-3-yl)methanone(210 mg, 1.03 mmol) was reacted with 2-fluoro-5-formyl benzoic acid (172mg, 1.03 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU, 507 mg, 1.33 mmol) and N,N-diisopropylethylamine (DIPEA, 0.36 mL, 2.05 mmol) to afford the intermediatecompound3-(3-(3,3-difluoropyrrolidine-1-carbonyl)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde(218 mg, 60%).

Step 2: Preparation of(Z)-3-(3-(3-(3,3-difluoropyrrolidine-1-carbonyl)pyrrolidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one

This compound was made using the procedure described for example 11(Step 2). Thus, this intermediate compound (Step 1)(218 mg, 0.62 mmol)was reacted withdimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (149 mg, 0.62mmol) and trietylamine (0.13 mL, 0.93 mmol) to afford the intermediatecompound(Z)-3-(3-(3-(3,3-difluoropyrrolidine-1-carbonyl)pyrrolidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one(139 mg, 48%).

Step 3: Preparation of4-(3-(3-(3,3-difluoropyrrolidine-1-carbonyl)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 11(Step 3). Thus, this intermediate compound (Step 2)(139 mg, 0.30 mmol)was reacted with hydrazine monohydrate (29 uL, 0.59 mmol) to afford thetitle compound (76 mg, 53%).

¹H-NMR (DMSO, 400 MHz): δ 12.60 (s, 1H), 8.26 (d, 1H), 7.98 (d, 1H),7.90 (t, 1H), 7.86-7.80 (m, 1H), 7.46-7.37 (m, 2H), 7.22 (t, 1H), 4.33(s, 2H), 4.08-3.98 (m, 1H), 3.79-3.67 (m, 2H), 3.64-3.42 (m, 3H),3.32-3.16 (m, 2H), 2.49-2.32 (m, 2H), 2.23-2.04 (m, 1H), 1.97-1.87 (m,1H), 1.18 (t, 1H).

Example 21(R)—N-(cyclopropylmethyl)-1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)ethyl)benzoyl)pyrrolidine-3-carboxamide;(I-21) Step 1: Preparation of(R)—N-(cyclopropylmethyl)-1-(2-fluoro-5-formylbenzoyl)pyrrolidine-3-carboxamide

This compound was made using the procedure described for example 11(Step 1). Thus, (R)—N-(cyclopropylmethyl)pyrrolidine-3-carboxamide (300mg, 1.78 mmol) was reacted with 2-fluoro-5-formyl benzoic acid (299 mg,1.78 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU, 879 mg, 2.32 mmol) and N,N-diisopropylethylamine (DIPEA, 0.63 mL, 3.57 mmol) to afford the intermediatecompound(R)—N-(cyclopropylmethyl)-1-(2-fluoro-5-formylbenzoyl)pyrrolidine-3-carboxamide(266 mg, 47%).

Step 2: Preparation of(R,Z)—N-(cyclopropylmethyl)-1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidine-3-carboxamide

This compound was made using the procedure described for example 11(Step 2). Thus, this intermediate compound (Step 1)(266 mg, 0.84 mmol)was reacted withdimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (203 mg, 0.84mmol) and trietylamine (0.18 mL, 1.26 mmol) to afford the intermediatecompound(R,Z)—N-(cyclopropylmethyl)-1-(2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidine-3-carboxamide(186 mg, 51%).

Step 3: Preparation of(R)—N-(cyclopropylmethyl)-1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidine-3-carboxamide

This compound was made using the procedure described for example 11(Step 3). Thus, this intermediate compound (Step 2)(186 mg, 0.43 mmol)was reacted with hydrazine monohydrate (42 uL, 0.85 mmol) to afford thetitle compound (84 mg, 44%).

¹H-NMR (MeOD, 400 MHz): δ 8.36-8.34 (m, 1H), 7.93 (t, 1H), 7.88-7.78 (m,2H), 7.47-7.39 (m, 2H), 7.14 (t, 1H), 4.37 (s, 2H), 3.82-3.53 (m, 2H),3.49-3.33 (m, 2H), 3.12-2.96 (m, 3H), 2.22-1.96 (m, 2H), 0.99-0.88 (m,1H), 0.52-0.44 (m, 2H), 2.24-2.02 (m, 2H).

Example 224-(4-fluoro-3-(3-(pyrrolidine-1-carbonyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-22) Step 1: Preparation of4-fluoro-3-(3-(pyrrolidine-1-carbonyl)azetidine-1-carbonyl)benzaldehyde

This compound was made using the procedure described for example 11(Step 1). Thus, azetidin-3-yl(pyrrolidin-1-yl)methanone (200 mg, 1.30mmol) was 2-fluoro-5-formyl benzoic acid (218 mg, 1.30 mmol),O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU, 639 mg, 1.69 mmol) and N,N-diisopropyl ethylamine (DIPEA, 0.45mL, 2.59 mmol) to afford the intermediate4-fluoro-3-(3-(pyrrolidine-1-carbonyl)azetidine-1-carbonyl)benzaldehyde(244 mg, 62%).

Step 2: Preparation of(Z)-3-(4-fluoro-3-(3-(pyrrolidine-1-carbonyl)azetidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one

This compound was made using the procedure described for example 11(Step 2). Thus, this intermediate compound (Step 1)(244 mg, 0.80 mmol)was reacted withdimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (194 mg, 0.80mmol) and trietylamine (0.17 mL, 1.21 mmol) to afford the intermediatecompound(Z)-3-(4-fluoro-3-(3-(pyrrolidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one(172 mg, 51%).

Step 3: Preparation of4-(4-fluoro-3-(3-(pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 11(Step 3). Thus, this intermediate compound (Step 2)(172 mg, 0.42 mmol)was reacted with hydrazine monohydrate (40 uL, 0.82 mmol) to afford thetitle compound (97 mg, 55%).

¹H-NMR (DMSO, 400 MHz): δ 12.61 (s, 1H), 8.37 (m, 1H), 7.24 (d, 1H),7.80-7.90 (m, 2H), 7.49 (m, 2H), 7.14 (t, 1H), 4.37 (s, 2H), 4.32 (t,1H), 4.22 (m, 3H), 3.71 (m, 1H), 3.44 (m, 2H), 3.30-3.44 (m, 2H),1.86-1.97 (m, 4H).

Example 23(R)-4-(3-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-23) Step 1: Preparation of(R)-3-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzaldehyde

This compound was made using the procedure described for example 11(Step 1). Thus,(R)-azetidin-3-yl(3-(dimethylamino)pyrrolidin-1-yl)methanone (200 mg,1.05 mmol) was reacted with 2-fluoro-5-formyl benzoic acid (176 mg, 2.05mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU, 515 mg, 1.36 mmol) and N,N-diisopropylethylamine (DIPEA, 0.52 mL, 2.98 mmol) to afford the intermediatecompound(R)-3-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzaldehyde(150 mg, 42%).

Step 2: Preparation of(R,Z)-3-(3-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one

This compound was made using the procedure described for example 11(Step 2). Thus, this intermediate compound (Step 1)(150 mg, 0.44 mmol)was reacted withdimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (106 mg, 0.44mmol) and trietylamine (92 uL, 0.65 mmol) to afford the intermediatecompound(R,Z)-3-(3-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one(102 mg, 51%).

Step 3: Preparation of(R)-4-(3-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 11(Step 3). Thus, this intermediate compound (Step 2)(102 mg, 0.22 mmol)was reacted with hydrazine monohydrate (21 uL, 0.45 mmol) to afford thetitle compound (53 mg, 50%).

¹H-NMR (MeOD, 400 MHz): δ 8.36 (m, 1H), 7.94-7.92 (m, 1H), 7.89-7.80 (m,2H), 7.56-7.39 (m, 2H), 7.16 (t, 1H), 4.36 (s, 2H), 4.20-4.03 (m, 2H),3.96-3.80 (m, 2H), 3.67 (m, 1H), 3.44 (t, 2H), 3.39-3.32 (m, 2H),2.98-2.90 (m, 1H), 2.10 (s, 6H), 1.82-1.80 (m, 2H).

Example 24(S)-4-(3-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-24) Step 1: Preparation of(S)-3-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzaldehyde

This compound was made using the procedure described for example 11(Step 1). Thus,(S)-azetidin-3-yl(3-(dimethylamino)pyrrolidin-1-yl)methanone (200 mg,1.05 mmol) was reacted with 2-fluoro-5-formyl benzoic acid (176 mg, 2.05mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU, 515 mg, 1.36 mmol) and N,N-diisopropylethylamine (DIPEA, 0.52 mL, 2.98 mmol) to afford the intermediatecompound(S)-3-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzaldehyde(150 mg, 42%).

Step 2: Preparation of(S,Z)-3-(3-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one

This compound was made using the procedure described for example 11(Step 2). Thus, this intermediate compound (Step 1)(150 mg, 0.44 mmol)was reacted withdimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (106 mg, 0.44mmol) and trietylamine (92 uL, 0.65 mmol) to afford the intermediatecompound(S,Z)-3-(3-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzylidene)isobenzofuran-1(3H)-one(102 mg, 51%).

Step 3: Preparation of(S)-4-(3-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 11(Step 3). Thus, this intermediate compound (Step 2)(102 mg, 0.22 mmol)was reacted with hydrazine monohydrate (21 uL, 0.45 mmol) to afford thetitle compound (53 mg, 50%).

¹H-NMR (MeOD, 400 MHz): δ 8.36 (m, 1H), 7.94-7.92 (m, 1H), 7.89-7.80 (m,2H), 7.56-7.39 (m, 2H), 7.16 (t, 1H), 4.36 (s, 2H), 4.20-4.03 (m, 2H),3.96-3.80 (m, 2H), 3.67 (m, 1H), 3.44 (t, 2H), 3.39-3.32 (m, 2H),2.98-2.90 (m, 1H), 2.10 (s, 6H), 1.82-1.80 (m, 2H).

Example 25 4-(3-(3-(cyclobutylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-25)Step 1: Preparation of4-(3-(3-(cyclobutylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

Cyclobutanone (42 uL, 0.57 mmol) was added to a solution of4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(100 mg, 0.28 mmol) in 1,2-dichloroethane (2 mL) and stirredfor 30 min then acetic acid (32 uL, 0.56 mmol) and triacetoxyborohydride(118 mg, 0.56 mmol) was added to the reaction mixture at 0° C. andstirred for 12 hours. The reaction mixture was concentrated in vacuum,added 2N NaOH(aq) and extracted into dichloromethane. The combinedorganic layers were dried over MgSO₄, filtered, evaporated in vacuum andpurified using silica chromatography to afford the title compound (82mg, 72%).

¹H-NMR (DMSO, 400 MHz): δ 12.61 (s, 1H), 8.26 (d, 1H), 7.97 (d, 1H),7.89 (t, 1H), 7.83 (t, 1H), 7.50-7.21 (m, 2H), 7.21 (t, 1H), 4.33 (s,2H), 4.10 (t, 1H), 3.97 (t, 1H), 3.67-3.51 (m, 3H), 3.08 (m, 1H), 2.76(m, 1H), 1.99 (t, 2H), 1.69-1.46 (m, 4H).

Example 264-(3-(3-(cyclopropylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-26) Step 1: Preparation of4-(3-(3-(cyclopropylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 25(Step 1). Thus,4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(200 mg, 0.57 mmol) was reacted with(1-ethoxycyclopropoxy)trimethylsilane(51 uL, 0.57 mmol) and sodiumtriacetoxyborohydride (248 mg, 1.17 mmol) to afford the title compound(152 mg, 68%).

¹H-NMR (MeOD, 400 MHz): δ 8.36 (d, 1H), 7.93 (d, 1H), 7.79-7.89 (m, 2H),7.48-7.54 (m, 1H), 7.42 (d, 1H), 7.15 (t, 1H), 4.00-4.05 (m, 2H),3.75-3.80 (m, 2H), 3.34-3.39 (m, 1H), 3.12 (s, 2H), 1.32-1.36 (m, 1H),0.64-0.72 (m, 2H), 0.41-0.46 (m, 2H).

Example 274-(3-(3-(cyclopentylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-27) Step 1: Preparation of4-(3-(3-(cyclopentylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 25(Step 1). Thus,4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(200 mg, 0.57 mmol) was reacted with cyclopentanone (51 uL,0.57 mmol) and sodium triacetoxyborohydride (248 mg, 1.178 mmol) toafford the title compound (240 mg, 66%).

¹H-NMR (DMSO, 400 MHz): δ 12.60 (s, 1H), 8.26 (d, 1H), 7.97 (d, 1H),7.89 (t, 1H), 7.83 (t, 1H), 7.44-7.50 (m, 1H), 7.40 (d, 1H), 7.21 (t,1H), 4.33 (s, 2H), 4.13 (t, 1H), 4.00 (t, 1H), 3.54-3.70 (m, 3H),2.82-2.91 (m, 1H), 1.52-1.67 (m, 4H), 1.43 (brs, 2H), 1.10-1.27 (m, 2H).

Example 284-(3-(3-(cyclohexylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-28) Step 1: Preparation of4-(3-(3-(cyclohexylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 25(Step 1). Thus,4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(200 mg, 0.57 mmol) was reacted with cyclohexanone (59 uL,0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) toafford the title compound (203 mg, 82%).

¹H-NMR (DMSO, 400 MHz): δ 12.61 (s, 1H), 8.26 (d, 1H), 7.97 (d, 1H),7.91-7.81 (m, 2H), 7.49-7.45 (m, 1H), 7.41-7.39 (m, 1H), 7.21 (t, 1H),4.33 (s, 2H), 4.16-3.98 (m, 2H), 3.67-3.58 (m, 3H), 2.33-2.26 (m, 1H),1.72-1.61 (m, 4H), 1.52 (d, 1H), 1.23-1.06 (m, 3H), 1.00-0.90 (m, 2H).

Example 29(R)-4-(3-(3-(cyclopropylamino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-29) Step 1: Preparation of(R)-4-(3-(3-(cyclopropylamino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 25(Step 1). Thus,(R)-4-(3-(3-aminopyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 1)(200 mg, 0.54 mmol) was reacted with(1-ethoxycyclopropoxy)tri methylsilane(49 uL, 0.54 mmol) and sodiumtriacetoxyborohydride (247 mg, 1.17 mmol) to afford the title compound(142 mg, 65%).

¹H-NMR (DMSO, 400 MHz): δ 12.60 (s, 1H), 8.27-8.25 (m, 1H), 7.97 (d,1H), 7.89-7.82 (m, 2H), 7.44-7.33 (m, 2H), 7.22 (t, 1H), 4.32 (s, 2H),3.29-3.23 (m, 2H), 3.15-2.99 (m, 1H), 2.06-1.73 (m, 3H), 1.24 (s, 1H),0.39-0.13 (m, 4H).

Example 30(R)-4-(3-(3-(cyclobutylamino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-30) Step 1: Preparation of(R)-4-(3-(3-(cyclobutylamino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 25(Step 1). Thus,(R)-4-(3-(3-aminopyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 1)(200 mg, 0.54 mmol) was reacted with cyclobutanone (41 uL,0.54 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) toafford the title compound (163 mg, 72%).

¹H-NMR (DMSO, 400 MHz): δ 12.60 (s, 1H), 8.26 (d, 1H), 7.97 (d, 1H),7.89 (t, 1H), 7.83 (t, 1H), 7.44-7.50 (m, 1H), 7.40 (d, 1H), 7.21 (t,1H), 4.37 (s, 2H), 3.79-3.67 (m, 1H), 3.59-3.33 (m, 3H), 3.29-3.06 (m,3H), 2.76 (m, 1H), 1.99 (t, 2H), 1.69-1.46 (m, 4H).

Example 31(R)-4-(3-(3-(cyclopentylamino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-31) Step 1: Preparation of(R)-4-(3-(3-(cyclopentylamino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 25(Step 1). Thus,(R)-4-(3-(3-aminopyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 1)(200 mg, 0.54 mmol) was reacted with cyclopentanone (48 uL,0.54 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) toafford the title compound (190 mg, 81%).

¹H-NMR (DMSO, 400 MHz): δ 12.60 (s, 1H), 8.26 (d, 1H), 7.97 (d, 1H),7.89 (t, 1H), 7.83 (t, 1H), 7.44-7.50 (m, 1H), 7.40 (d, 1H), 7.21 (t,1H), 4.37 (s, 2H), 3.79-3.67 (m, 1H), 3.59-3.33 (m, 3H), 3.29-3.06 (m,3H), 2.82-2.91 (m, 1H), 1.52-1.67 (m, 4H), 1.43 (brs, 2H), 1.10-1.27 (m,2H).

Example 324-(4-fluoro-3-(3-(isopropylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-32) Step 1: Preparation of4-(4-fluoro-3-(3-(isopropylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 25(Step 1). Thus,4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(200 mg, 0.57 mmol) was reacted with acetone (42 uL, 0.57mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) to afford thetitle compound (123 mg, 55%).

¹H-NMR (DMSO, 400 MHz): δ 12.61 (s, 1H), 8.27-8.25 (m, 1H), 7.97 (d,1H), 7.91-7.81 (m, 2H), 7.48-7.44 (m, 1H), 7.41-7.39 (m, 1H), 7.21 (t,1H), 4.33 (s, 2H), 4.15-4.10 (m, 2H), 3.66-3.59 (m, 3H), 3.17 (d, 1H),2.68-2.61 (m, 1H), 0.92-0.83 (m, 6H).

Example 334-(3-(3-((cyclopropylmethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-33) Step 1: Preparation of4-(3-(3-((cyclopropylmethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 25(Step 1). Thus,4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(200 mg, 0.57 mmol) was reacted with cyclopropanecarbaldehyde(42 uL, 0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol)to afford the title compound (153 mg, 66%).

¹H-NMR (DMSO, 400 MHz): δ 12.61 (s, 1H), 8.28-7.97 (m, 2H), 7.91-7.81(m, 2H), 7.48-7.40 (m, 2H), 7.22 (m, 1H), 4.33 (s, 2H), 4.13-3.98 (m,2H), 3.70-3.56 (m, 3H), 2.29 (m, 2H), 0.83-0.72 (m, 1H), 0.37-0.32 (m,2H), 0.06 (m, 2H).

Example 344-(3-(3-(bis(cyclopropylethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-34) Step 1: Preparation of4-(3-(3-(bis(cyclopropylmethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 25(Step 1). Thus,4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(200 mg, 0.57 mmol) was reacted with cyclopropanecarbaldehyde(84 uL, 1.14 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol)to afford the title compound (116 mg, 43%).

¹H-NMR (DMSO, 400 MHz): δ 12.57 (s, 1H), 8.23 (m, 1H), 7.97-7.77 (m,3H), 7.47-7.36 (m, 2H), 7.18 (m, 1H), 4.29 (s, 2H), 3.99 (m, 1H),3.88-3.58 (m, 4H), 2.38-2.31 (m, 4H), 0.77 (m, 2H), 0.38 (s, 2H), 0.36(s, 2H), 0.01 (s, 4H).

Example 354-(4-fluoro-3-(3-(isobutylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-35) Step 1: Preparation of4-(4-fluoro-3-(3-(isobutylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 25(Step 1). Thus,4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(200 mg, 0.57 mmol) was reacted with isobutyraldehyde (52 uL,0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) toafford the title compound (194 mg, 83%).

¹H-NMR (MeOD, 400 MHz): δ 8.38-8.35 (m, 1H), 7.95-7.93 (m, 1H),7.89-7.82 (m, 2H), 7.51-7.49 (m, 1H), 7.45-7.43 (m, 1H), 7.15 (t, 1H),4.38 (s, 2H), 4.28-4.26 (m, 1H), 4.16-4.12 (m, 1H), 3.88-3.84 (m, 1H),3.79-3.75 (m, 1H), 3.66-3.64 (m, 1H), 2.31-2.28 (m, 2H), 1.71-1.68 (m,1H), 0.91 (dd, 6H).

Example 364-(4-fluoro-3-(3-((1-hydroxypropan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-36) Step 1: Preparation of4-(4-fluoro-3-(3-((1-hydroxypropan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 25(Step 1). Thus,4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(200 mg, 0.57 mmol) was reacted with 1-hydroxypropan-2-one(39 uL, 0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol)to afford the title compound (82 mg, 35%).

¹H-NMR (MeOD, 400 MHz): δ 8.36-8.34 (m, 1H), 7.94-7.92 (m, 1H),7.88-7.81 (m, 2H), 7.50-7.49 (m, 1H), 7.46-7.44 (m, 1H), 7.16-7.11 (m,1H), 4.36 (s, 2H), 4.35-4.33 (m, 1H), 4.20-4.17 (m, 1H), 3.90-3.3.83 (m,3H), 3.46-3.43 (m, 1H), 3.39-3.36 (m, 1H), 2.77-2.75 (m, 1H), 1.95 (s,1H), 1.02 (q, 3H).

Example 37 4-(4-fluoro-3-(3-(neopentylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-37) Step 1:Preparation of4-(4-fluoro-3-(3-(neopentylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 25(Step 1). Thus,4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(200 mg, 0.57 mmol) was reacted with pivalaldehyde (62 uL,0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) toafford the title compound (185 mg, 77%).

¹H-NMR (MeOD, 400 MHz): δ 8.34 (m, 1H), 7.92-7.78 (m, 3H), 7.50-7.43 (m,2H), 7.13 (t, 1H), 4.35 (s, 2H), 4.29-4.10 (m, 2H), 3.88-3.75 (m, 2H),3.62 (m, 1H), 2.23 (m, 2H), 0.91 (s, 9H).

Example 384-(3-(3-((2,2-dimethylcyclopentyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-38) Step 1: Preparation of4-(3-(3-((2,2-dimethylcyclopentyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 25(Step 1). Thus,4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(200 mg, 0.57 mmol) was reacted with2,2-dimethylcyclopentanone (72 uL, 0.57 mmol) and sodiumtriacetoxyborohydride (247 mg, 1.17 mmol) to afford the title compound(99 mg, 39%).

¹H-NMR (MeOD, 400 MHz): δ 8.35 (m, 1H), 7.93-7.79 (m, 3H), 7.51-7.42 (m,2H), 7.14 (t, 1H), 4.36 (s, 2H), 4.30-4.10 (m, 2H), 3.90-3.68 (m, 3H),2.43 (m, 1H), 1.95-1.82 (m, 1H), 1.68-1.28 (m, 5H), 1.01 (d, 3H), 0.84(s, 3H).

Example 39 ethyl2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)cyclopent-1-enecarboxylate;(I-39) Step 1: Preparation of ethyl2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)cyclopent-1-enecarboxylate

This compound was made using the procedure described for example 25(Step 1). Thus,4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(200 mg, 0.57 mmol) was reacted with ethyl2-oxocyclopentanecarboxylate (85 uL, 0.57 mmol) and sodiumtriacetoxyborohydride (247 mg, 1.17 mmol) to afford the title compound(64 mg, 23%).

¹H-NMR (CDCl₃, 400 MHz): δ 11.44 (s, 1H), 8.48 (m, 1H), 7.80-7.73 (m,3H), 7.55 (m, 1H), 7.34-7.28 (m, 1H), 7.01 (t, 1H), 4.50 (t, 1H),4.39-4.27 (m, 4H), 4.15 (m, 2H), 4.01 (m, 2H), 2.52-2.38 (m, 4H),1.86-1.80 (m, 2H), 1.28 (t, 3H).

Example 40 4-(4-fluoro-3-(3-(pentan-3-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-40) Step 1:Preparation of4-(4-fluoro-3-(3-(pentan-3-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 25(Step 1). Thus,4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(200 mg, 0.57 mmol) was reacted with pentan-3-one (48 uL,0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) toafford the title compound (46 mg, 19%).

¹H-NMR (CDCl₃, 400 MHz): δ 11.32 (br, 1H), 8.47 (m, 1H), 7.77-7.72 (m,3H), 7.51 (m, 1H), 7.32-7.31 (m, 1H), 7.00 (t, 1H), 4.39 (m, 1H), 4.29(s, 2H), 4.17 (m, 1H), 3.85-3.74 (m, 3H), 2.36 (m, 1H), 2.06 (br, 1H),1.38 (m, 4H), 0.87 (dd, 6H).

Example 414-(4-fluoro-3-(3-((3-ethylbutan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-41) Step 1: Preparation of4-(4-fluoro-3-(3-((3-methylbutan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 25(Step 1). Thus,4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(200 mg, 0.57 mmol) was reacted with 3-methylbutan-2-one (61uL, 0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) toafford the title compound (125 mg, 52%).

¹H-NMR (CDCl₃, 400 MHz): δ 11.22 (s, 1H), 8.50-8.45 (m, 1H), 7.79-7.71(m, 3H), 7.52-7.50 (m, 1H), 7.33-7.29 (m, 1H), 7.01 (t, 1H), 4.38 (m,1H), 4.29 (s, 2H), 4.21-4.13 (m, 1H), 3.86-3.72 (m, 3H), 2.50-2.40 (m,1H), 1.66-1.55 (m, 1H), 0.94-0.84 (m, 9H).

Example 424-(3-(3-((1-cyclopropylethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-42) Step 1: Preparation of4-(3-(3-((1-cyclopropylethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 25(Step 1). Thus,4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(200 mg, 0.57 mmol) was reacted with 1-cyclopropylethanone(56 uL, 0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol)to afford the title compound (239 mg, 43%).

¹H-NMR (CDCl₃, 400 MHz): δ 11.18 (s, 1H), 8.49-8.47 (m, 1H), 7.79-7.72(m, 3H), 7.52-7.50 (m, 1H), 7.33-7.29 (m, 1H), 7.01 (t, 1H), 4.40 (m,1H), 4.29 (s, 2H), 3.79 (m, 1H), 1.93 (br, 1H), 1.83 (m, 1H), 1.14 (m,3H), 0.70-0.40 (m, 3H), 0.15-0.04 (m, 2H).

Example 434-(3-(3-(bicyclo[2.2.1]heptan-2-ylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-43) Step 1: Preparation of4-(3-(3-(bicyclo[2.2.1]heptan-2-ylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 25(Step 1). Thus,4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(200 mg, 0.57 mmol) was reacted with norcamphor (62 mg, 0.57mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) to afford thetitle compound (48 mg, 19%).

¹H-NMR (MeOD, 400 MHz): δ 8.37 (d, 1H), 7.92 (d, 1H), 7.82-7.88 (m, 2H),7.48-7.50 (m, 1H), 7.41-7.43 (m, 1H), 7.14 (t, 1H), 4.38 (s, 2H),4.28-4.37 (m, 1H), 4.09-4.26 (m, 1H), 3.70-3.91 (m, 2H), 3.61-3.69 (m,1H), 2.88-2.95 (m, 1H), 2.14-2.23 (m, 2H), 1.73-1.94 (m, 2H), 1.48-1.71(m, 2H), 1.22-1.40 (m, 4H).

Example 44 4-(3-(3-(sec-butylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-44)Step 1: Preparation of4-(3-(3-(sec-butylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 25(Step 1). Thus,4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(200 mg, 0.57 mmol) was reacted with butan-2-one (51 uL, 0.57mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) to afford thetitle compound (74 mg, 32%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.58 (s, 1H), 8.49-8.45 (m, 1H), 7.80-7.71(m, 3H), 7.52-7.49 (dd, 1H), 7.33-7.30 (m, 1H), 7.01 (t, 1H), 4.44-4.35(m, 1H), 4.28 (s, 2H), 4.22-4.14 (m, 1H), 3.86-3.73 (m, 3H), 2.59-2.52(m, 1H), 1.48-1.24 (m, 3H), 1.02-0.98 (m, 3H), 0.91-0.86 (m, 3H).

Example 454-(3-(3-((dicyclopropylmethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-45) Step 1: Preparation of4-(3-(3-((dicyclopropylmethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 25(Step 1). Thus,4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(200 mg, 0.57 mmol) was reacted with dicyclopropylmethanone(43 uL, 0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol)to afford the title compound (28 mg, 11%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.63 (s, 1H), 8.50-8.45 (m, 1H), 7.87-7.71(m, 3H), 7.52-7.50 (m, 1H), 7.33-7.31 (m, 1H), 7.01 (t, 1H), 4.41-4.37(m, 1H), 4.28 (s, 2H), 4.20-4.16 (m, 1H), 3.99-3.93 (m, 1H), 3.89-3.76(m, 2H), 1.74 (br, 1H), 1.08 (t, 1H), 0.85-0.77 (m, 2H), 0.54-0.42 (m,4H), 0.24-0.18 (m, 2H), 0.08-0.04 (m, 2H).

Example 464-(4-fluoro-3-(3-((4-ethylpentan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-46) Step 1: Preparation of4-(4-fluoro-3-(3-((4-methylpentan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 25(Step 1). Thus,4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(200 mg, 0.57 mmol) was reacted with 4-methylpentan-2-one (57mg, 0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) toafford the title compound (104 mg, 42%).

¹H-NMR (MeOD, 400 MHz): δ 8.37-8.35 (m, 1H), 7.95-7.92 (m, 1H),7.87-7.82 (m, 2H), 7.51-7.49 (m, 1H), 7.45-7.43 (m, 1H), 7.16 (q, 1H),4.37 (s, 2H), 4.34-4.32 (m, 1H), 4.19-4.17 (m, 1H), 3.84-3.82 (m, 3H),2.78-2.76 (m, 1H), 1.71-1.68 (m, 1H), 1.32-1.27 (m, 2H), 1.03-0.99 (m,3H), 0.92-0.86 (m, 6H).

Example 474-(4-fluoro-3-(3-((3-hydroxybutan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-47) Step 1: Preparation of4-(4-fluoro-3-(3-((3-hydroxybutan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 25(Step 1). Thus,4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(200 mg, 0.57 mmol) was reacted with 3-hydroxybutan-2-one (49uL, 0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) toafford the title compound (60 mg, 25%).

¹H-NMR (MeOD, 400 MHz): δ 8.38-8.36 (m, 1H), 7.94-7.92 (m, 1H),7.88-7.80 (m, 2H), 7.52-7.49 (m, 1H), 7.46-7.44 (m, 1H), 7.16-7.11 (m,1H), 4.37 (s, 2H), 4.35-4.32 (m, 1H), 4.19-4.16 (m, 1H), 3.91-3.89 (m,3H), 2.04-1.99 (m, 2H), 1.15-1.12 (m, 3H), 0.12-0.95 (m, 3H).

Example 48 4-(4-fluoro-3-(3-(pentan-2-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-48) Step 1:Preparation of4-(4-fluoro-3-(3-(pentan-2-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 25(Step 1). Thus,4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(200 mg, 0.57 mmol) was reacted with pentan-2-one (49 mg,0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) toafford the title compound (113 mg, 51%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.55 (s, 1H), 8.49-8.45 (m, 1H), 7.80-7.71(m, 3H), 7.50 (d, 1H), 7.33-7.29 (m, 1H), 7.01 (t, 1H), 4.42-4.36 (m,1H), 4.21-4.11 (m, 1H), 3.85-3.72 (m, 3H), 2.66-2.59 (m, 1H), 1.40-1.25(m, 5H), 1.02-0.98 (m, 3H), 0.92-0.88 (m, 3H).

Example 494-(4-fluoro-3-(3-((1-(1-methylcyclopropyl)ethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-49) Step 1: Preparation of4-(4-fluoro-3-(3-((1-(1-methylcyclopropyl)ethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 25(Step 1). Thus,4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(200 mg, 0.57 mmol) was reacted with1-(1-methylcyclopropyl)ethanone (63 uL, 0.57 mmol) and sodiumtriacetoxyborohydride (247 mg, 1.17 mmol) to afford the title compound(37 mg, 16%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.22 (s, 1H), 8.48-8.45 (m, 1H), 7.78-7.71(m, 3H), 7.50-7.49 (m, 1H), 7.33-7.29 (m, 1H), 7.02 (t, 1H), 4.40-4.34(m, 1H), 4.27 (s, 2H), 4.15 (t, 1H), 3.84-3.73 (m, 3H), 1.85-1.79 (m,1H), 1.41 (br, 1H), 1.10-1.07 (dd, 3H), 0.97-0.95 (d, 3H).

Example 50 4-(4-fluoro-3-(3-((3,3,3-trifluoro-2-ethylpropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-50) Step 1: Preparation of4-(4-fluoro-3-(3-((3,3,3-trifluoro-2-methylpropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 25(Step 1). Thus,4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(200 mg, 0.57 mmol) was reacted with3,3,3-trifluoro-2-methylpropanal (0.1 uL, 0.57 mmol) and sodiumtriacetoxyborohydride (247 mg, 1.17 mmol) to afford the title compound(137 mg, 52%).

¹H-NMR (MeOD, 400 MHz): δ 8.26 (d, 1H), 7.72-7.84 (m, 3H), 7.33-7.41 (m,2H), 7.04 (t, 1H), 4.28 (s, 2H), 4.18 (t, 1H), 4.02-4.05 (m, 1H),3.71-3.76 (m, 1H), 3.63-3.67 (m, 1H), 3.54-3.58 (m, 1H), 2.65-2.70 (m,1H), 2.32-2.38 (m, 2H), 1.05-1.07 (m, 3H).

Example 51 4-(3-(3-(allylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-51)Step 1: Preparation of4-(3-(3-(allylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 25(Step 1). Thus,4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(200 mg, 0.57 mmol) was reacted with acrylaldehyde (38 uL,0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) toafford the title compound (147 mg, 66%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.02 (s, 1H), 8.40-8.38 (m, 1H), 7.72-7.64(m, 3H), 7.44-7.42 (m, 1H), 7.25-7.22 (m, 1H), 6.97-6.93 (m, 1H), 5.79(m, 1H), 5.13-5.03 (m, 2H), 4.30-4.27 (m, 1H), 4.20 (s, 2H), 4.10-4.08(m, 1H), 3.83-3.79 (m, 1H), 3.72-3.65 (m, 2H), 3.14 (d, 2H).

Example 524-(4-fluoro-3-(3-(isopentylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-52) Step 1: Preparation of4-(4-fluoro-3-(3-(isopentylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 25(Step 1). Thus,4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(200 mg, 0.57 mmol) was reacted with 3-methylbutanal (61 uL,0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) toafford the title compound (190 mg, 79%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.14 (s, 1H), 8.47-8.45 (m, 1H), 7.79-7.71(m, 3H), 7.50 (m, 1H), 7.33-7.29 (m, 1H), 7.02 (t, 1H), 4.36 (t, 1H),4.27 (s, 2H), 4.18 (t, 1H), 3.88-3.68 (m, 3H), 2.56 (m, 2H), 1.62 (m,1H), 1.51 (br, 1H), 1.38-1.35 (m, 2H), 0.90-0.88 (dd, 6H).

Example 534-(3-(3-(butylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-53) Step 1: Preparation of4-(3-(3-(butylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 25(Step 1). Thus,4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(200 mg, 0.57 mmol) was reacted with butyraldehyde (51 uL,0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) toafford the title compound (198 mg, 85%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.28 (s, 1H), 8.40-8.38 (m, 1H), 7.72-7.66(m, 1H), 7.44-7.41 (m, 1H), 7.24-7.22 (m, 1H), 6.97-6.92 (m, 1H),4.30-4.27 (m, 1H), 4.20 (s, 2H), 4.11-4.09 (m, 1H), 3.81-3.79 (m, 1H),3.72-3.70 (m, 1H), 3.64-3.62 (m, 1H), 2.50-2.46 (m, 2H), 2.02 (s, 1H),1.40-1.37 (m, 2H), 1.30-1.24 (m, 2H), 0.86-0.80 (m, 5H).

Example 544-(4-fluoro-3-(3-((3-ethylbut-2-en-1-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-54) Step 1: Preparation of4-(4-fluoro-3-(3-((3-methylbut-2-en-1-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 25(Step 1). Thus,4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(200 mg, 0.57 mmol) was reacted with 3-methylbut-2-enal (55uL, 0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) toafford the title compound (146 mg, 61%).

¹H-NMR (MeOD, 400 MHz): δ 8.36 (d, 1H), 7.79-7.94 (m, 3H), 7.43-7.51 (m,2H), 7.13 (t, 1H), 5.19 (brs, 1H), 4.37 (s, 2H), 4.26 (t, 1H), 4.13 (t,1H), 3.83-3.87 (m, 1H), 3.74-3.78 (m, 1H), 3.63-3.66 (m, 1H), 3.11 (d,2H), 1.71 (s, 3H), 1.64 (s, 3H).

Example 554-(3-(3-((cyclopentylmethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-55) Step 1: Preparation of4-(3-(3-((cyclopentylmethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 25(Step 1). Thus,4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(200 mg, 0.57 mmol) was reacted with cyclopentanecarbaldehyde(61 uL, 0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol)to afford the title compound (178 mg, 72%).

¹H-NMR (MeOD, 400 MHz): δ 8.38-8.36 (m, 1H), 7.94-7.93 (m, 1H),7.89-7.82 (m, 2H), 7.51-7.43 (m, 2H), 7.17-7.12 (m, 1H), 4.38 (s, 2H),4.29-4.28 (m, 1H), 4.15-4.13 (m, 1H), 3.88-3.87 (m, 1H), 3.79-3.77 (m,1H), 3.66-3.64 (m, 1H), 2.45-2.42 (m, 2H), 1.98-1.95 (m, 1H), 1.81-1.79(m, 2H), 1.65-1.56 (m, 4H), 1.18-1.16 (m, 2H).

Example 564-(4-fluoro-3-(3-((4,4,4-trifluorobutyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2)-one;(I-56) Step 1: Preparation of4-(4-fluoro-3-(3-((4,4,4-trifluorobutyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 25(Step 1). Thus,4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(200 mg, 0.57 mmol) was reacted with 4,4,4-trifluorobutanol(72 mg, 0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol)to afford the title compound (111 mg, 42%).

¹H-NMR (MeOD, 400 MHz): δ 8.38-8.35 (m, 1H), 7.95-7.92 (m, 1H),7.89-7.82 (m, 2H), 7.52-7.50 (m, 1H), 7.45-7.43 (m, 1H), 7.17-7.12 (m,1H), 4.37 (s, 2H), 4.30-4.28 (m, 1H), 4.16-4.14 (m, 1H), 3.86-3.83 (m,1H), 3.78-3.76 (m, 1H), 3.68-3.66 (m, 1H), 2.58-2.55 (m, 2H), 2.24-2.17(m, 2H), 1.74-1.68 (m, 2H).

Example 57 4-(4-fluoro-3-(3-(pentyl amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-57) Step 1: Preparation of4-(4-fluoro-3-(3-(pentylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 25(Step 1). Thus,4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(200 mg, 0.57 mmol) was reacted with pentanal (61 uL, 0.57mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) to afford thetitle compound (200 mg, 83%).

¹H-NMR (MeOD, 400 MHz): δ 8.38-8.35 (m, 1H), 7.94-7.92 (m, 1H),7.89-7.82 (m, 2H), 7.51-7.49 (m, 1H), 7.45-7.43 (m, 1H), 7.17-7.12 (m,1H), 4.37 (s, 2H), 4.30-4.28 (m, 1H), 4.17-4.15 (m, 1H), 3.88-3.86 (m,1H), 3.80-3.78 (m, 1H), 3.69-3.67 (m, 1H), 2.53-2.49 (m, 2H), 1.51-1.47(m, 2H), 1.35-1.29 (m, 4H), 0.91 (t, 3H).

Example 584-(3-(3-((2-cyclopropylethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-58) Step 1: Preparation of4-(3-(3-((2-cyclopropylethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 25(Step 1). Thus,4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(200 mg, 0.57 mmol) was reacted with2-cyclopropylacetaldehyde (48 mg, 0.57 mmol) and sodiumtriacetoxyborohydride (247 mg, 1.17 mmol) to afford the title compound(240 mg, 69%).

¹H-NMR (MeOD, 400 MHz): δ 8.38-8.36 (m, 1H, 7.95-7.93 (m, 1H), 7.89-7.82(m, 2H), 7.52-7.50 (m, 1H), 7.45-7.43 (m, 1H), 7.17-7.15 (m, 1H), 4.38(s, 2H), 4.30-4.29 (m, 1H), 4.15-4.14 (m, 1H), 3.87-3.86 (m, 1H),3.78-3.77 (m, 1H), 3.68-3.66 (m, 1H), 2.60-2.56 (m, 2H), 1.39-1.34 (m,2H), 0.72-0.71 (m, 1H), 0.46-0.42 (m, 2H), 0.06-0.04 (m, 2H).

Example 59 4-(4-fluoro-3-(3-(propylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-59) Step 1:Preparation of4-(4-fluoro-3-(3-(propylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 25(Step 1). Thus,4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(200 mg, 0.57 mmol) was reacted with propionaldehyde (42 uL,0.57 mmol) and sodium triacetoxyborohydride (247 mg, 1.17 mmol) toafford the title compound (191 mg, 85%).

¹H-NMR (MeOD, 400 MHz): δ 10.39 (s, 1H), 8.47-8.45 (m, 1H), 7.80-7.72(m, 3H), 7.51-7.48 (m, 1H), 7.33-7.29 (m, 1H), 7.04-6.99 (m, 1H),4.39-4.34 (m, 1H), 4.27 (s, 2H), 4.19-4.17 (m, 1H), 3.89-3.85 (m, 1H),3.81-3.77 (m, 1H), 3.71-3.70 (m, 1H), 2.55-2.50 (m, 2H), 1.52-1.47 (m,2H), 0.94-0.91 (m, 3H).

Example 604-(4-fluoro-3-(3-(methyl(pyridin-4-ylmethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-60) Step 1: Preparation of4-(4-fluoro-3-(3-((pyridin-4-ylmethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

isonicotinaldehyde (26 uL, 0.28 mmol) was added to a solution of4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(100 mg, 0.28 mmol) in 1,2-dichloroethane (1.1 mL) andstirred for 30 min then acetic acid (31 uL, 0.54 mmol) and sodiumtriacetoxyborohydride (114 mg, 0.54 mmol) was added to the reactionmixture at 0° C. and stirred for 12 hours. The reaction mixture wasconcentrated in vacuum, added 2N NaOH(aq) and extracted intodichloromethane. The combined organic layers were dried over MgSO₄,filtered, evaporated in vacuum and purified using silica chromatographyto afford the intermediate compound4-(4-fluoro-3-(3-((pyridin-4-ylmethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one(108 mg, 87%).

Step 2: Preparation of4-(4-fluoro-3-(3-(methyl(pyridin-4-ylmethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

K₂CO₃ (51 mg, 0.48 mmol) and iodomethane (33 uL, 0.48 mmol) was added toa solution of the intermediate compound (Step 1)(108 mg, 0.24 mmol) inDMF (1.5 mL) and stirred for 3 hours. The reaction mixture wasconcentrated in vacuum, added dichloromethane and washed sat. NH₄Cl (aq)and water. The combined organic layers were dried over MgSO₄, filtered,evaporated in vacuum and purified using silica chromatography to affordthe title compound (99 mg, 91%).

¹H-NMR (MeOD, 400 MHz): δ 8.47 (d, 2H), 8.36 (d, 2H), 7.94 (d, 1H),7.78-7.91 (m, 2H), 7.40-7.55 (m, 3H), 7.15 (t, 1H), 4.38 (s, 2H),4.18-4.25 (m, 1H), 3.97-4.14 (m, 2H), 3.80-3.90 (m, 1H), 3.42-3.54 (m,3H), 2.08 (s, 3H).

Example 61(R)-4-(4-fluoro-3-(3-(methyl(pyridin-4-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-61) Step 1: Preparation of(R)-4-(4-fluoro-3-(3-((pyridin-4-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 60(Step 1). Thus,(R)-4-(3-(3-aminopyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 1)(100 mg, 0.28 mmol) was reacted with isonicotinaldehyde (26uL, 0.28 mmol) and sodium triacetoxyborohydride (114 mg, 0.54 mmol) toafford the intermediate compound(R)-4-(4-fluoro-3-(3-((pyridin-4-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one(106 mg, 83%).

Step 2: Preparation of(R)-4-(4-fluoro-3-(3-(methyl(pyridin-4-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 60(Step 2). Thus, this intermediate compound (Step 1)(106 mg, 0.23 mmol)was reacted with K₂CO₃ (51 mg, 0.48 mmol) and iodomethane (33 uL, 0.48mmol) to afford the title compound (98 mg, 91%).

¹H-NMR (DMSO, 400 MHz): δ 12.61 (s, 1H), 8.51-8.47 (m, 2H), 8.26 (t,1H), 7.97 (m, 1H), 7.92-7.78 (m, 2H), 7.45-7.33 (m, 3H), 7.24 (m, 2H),4.32 (s, 2H), 3.76 (m, 1H), 3.51 (m, 3H), 3.30 (s, 2H), 3.08 (m, 1H),1.92 (s, 3H), 1.81 (m, 2H),

Example 62(S)-4-(4-fluoro-3-(3-(methyl(pyridin-4-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-62) Step 1: Preparation of(S)-4-(4-fluoro-3-(3-((pyridin-4-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 60(Step 1). Thus,(S)-4-(3-(3-aminopyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 2)(100 mg, 0.23 mmol) was reacted with isonicotinaldehyde (33uL, 0.23 mmol) and sodium triacetoxyborohydride (114 mg, 0.54 mmol) toafford the intermediate compound(S)-4-(4-fluoro-3-(3-((pyridin-4-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one(106 mg, 83%).

Step 2: Preparation of(S)-4-(4-fluoro-3-(3-(methyl(pyridin-4-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 60(Step 2). Thus, this intermediate compound (Step 1)(106 mg, 0.24 mmol)was reacted with K₂CO₃ (51 mg, 0.48 mmol) and iodomethane (33 uL, 0.48mmol) to afford the title compound (98 mg, 91%).

¹H-NMR (DMSO, 400 MHz): δ 12.61 (s, 1H), 8.51-8.47 (m, 2H), 8.26 (t,1H), 7.97 (m, 1H), 7.92-7.78 (m, 2H), 7.45-7.33 (m, 3H), 7.24 (m, 2H),4.32 (s, 2H), 3.76 (m, 1H), 3.51 (m, 3H), 3.30 (s, 2H), 3.08 (m, 1H),1.92 (s, 3H), 1.81 (m, 2H), 1.19 (m, 1H).

Example 63(S)-4-(4-fluoro-3-(3-(methyl(pyridin-2-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-63) Step 1: Preparation of(S)-4-(4-fluoro-3-(3-((pyridin-2-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 60(Step 1). Thus,(S)-4-(3-(3-aminopyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 2)(100 mg, 0.23 mmol) was reacted with picolinaldehyde (33 uL,0.23 mmol) and sodium triacetoxyborohydride (114 mg, 0.54 mmol) toafford the intermediate compound(S)-4-(4-fluoro-3-(3-((pyridin-2-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one(85 mg, 81%).

Step 2: Preparation of(S)-4-(4-fluoro-3-(3-(methyl(pyridin-2-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 60(Step 2). Thus, this intermediate compound (Step 1)(85 mg, 0.19 mmol)was reacted with K₂CO₃ (51 mg, 0.37 mmol) and iodomethane (23 uL, 0.37mmol) to afford the title compound (79 mg, 88%).

¹H-NMR (MeOD, 400 MHz): δ 10.82 (s, 0.4H), 10.40 (s, 0.6H), 8.62 (dd,1H), 8.46 (m, 1H), 7.75 (m, 3H), 7.52 (m, 1H), 7.37 (m, 2H), 7.17 (m,1H), 7.0 (m, 1H), 4.15 (s, 2H), 3.96 (m, 1H), 3.89 (m, 1H), 3.74 (d,1H), 3.63 (m, 2H), 3.46 (m, 1H), 3.41 (m, 1H), 2.21 (s, 2H), 1.93 (m,3H).

Example 64(R)-4-(4-fluoro-3-(3-(methyl(pyridin-2-ylethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-64) Step 1: Preparation of(R)-4-(4-fluoro-3-(3-((pyridin-2-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 60(Step 1). Thus,(R)-4-(3-(3-aminopyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 1)(100 mg, 0.23 mmol) was reacted with picolinaldehyde (33 uL,0.23 mmol) and sodium triacetoxyborohydride (114 mg, 0.54 mmol) toafford the intermediate compound(R)-4-(4-fluoro-3-(3-((pyridin-2-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one(85 mg, 81%).

Step 2: Preparation of(R)-4-(4-fluoro-3-(3-(methyl(pyridin-2-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 60(Step 2). Thus, this intermediate compound (Step 1)(85 mg, 0.19 mmol)was reacted with K₂CO₃ (51 mg, 0.37 mmol) and iodomethane (23 uL, 0.37mmol) to afford the title compound (79 mg, 88%).

¹H-NMR (MeOD, 400 MHz): δ 10.82 (s, 0.4H), 10.40 (s, 0.6H), 8.62 (dd,1H), 8.46 (m, 1H), 7.75 (m, 3H), 7.52 (m, 1H), 7.37 (m, 2H), 7.17 (m,1H), 7.0 (m, 1H), 4.15 (s, 2H), 3.96 (m, 1H), 3.89 (m, 1H), 3.74 (d,1H), 3.63 (m, 2H), 3.46 (m, 1H), 3.41 (m, 1H), 2.21 (s, 2H), 1.93 (m,3H).

Example 654-(4-fluoro-3-(3-(methyl(pyridin-2-ylmethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-65) Step 1: Preparation of4-(4-fluoro-3-(3-((pyridin-2-ylmethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 60(Step 1). Thus,4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(100 mg, 0.28 mmol) was reacted with picolinaldehyde (26 uL,0.28 mmol) and sodium triacetoxyborohydride (114 mg, 0.54 mmol) toafford the intermediate compound4-(4-fluoro-3-(3-((pyridin-2-ylmethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one(108 mg, 87%).

Step 2: Preparation of4-(4-fluoro-3-(3-(methyl(pyridin-2-ylmethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 60(Step 2). Thus, this intermediate compound (Step 1)(108 mg, 0.24 mmol)was reacted with K₂CO₃ (51 mg, 0.48 mmol) and iodomethane (33 uL, 0.48mmol) to afford the title compound (99 mg, 91%).

¹H-NMR (MeOD, 400 MHz): δ 8.47 (d, 1H), 8.35 (d, 1H), 7.94 (d, 1H),7.78-7.89 (m, 3H), 7.43-7.54 (m, 3H), 7.30-7.35 (m, 1H), 7.14 (t, 1H),4.38 (s, 2H), 4.17-4.22 (m, 1H), 3.95-4.06 (m, 2H), 3.87-3.94 (m, 1H),3.57 (s, 2H), 3.44-3.51 (m, 1H), 2.18 (s, 3H).

Example 664-(4-fluoro-3-(3-(methyl(pyridin-3-ylmethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-66) Step 1: Preparation of4-(4-fluoro-3-(3-((pyridin-3-ylmethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 60(Step 1). Thus,4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(100 mg, 0.28 mmol) was reacted with nicotinaldehyde (26 uL,0.28 mmol) and sodium triacetoxyborohydride (114 mg, 0.54 mmol) toafford the intermediate compound4-(4-fluoro-3-(3-((pyridin-3-ylmethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one(108 mg, 87%).

Step 2: Preparation of4-(4-fluoro-3-(3-(methyl(pyridin-3-ylmethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 60(Step 2). Thus, this intermediate compound (Step 1)(108 mg, 0.24 mmol)was reacted with K₂CO₃ (51 mg, 0.48 mmol) and iodomethane (33 uL, 0.48mmol) to afford the title compound (99 mg, 91%).

¹H-NMR (MeOD, 400 MHz): δ 8.43-8.51 (m, 2H), 8.36 (d, 1H), 7.94 (d, 1H),7.79-7.90 (m, 3H), 7.48-7.53 (m, 1H), 7.39-7.48 (m, 2H), 7.15 (t, 1H),4.38 (s, 2H), 4.18-4.25 (m, 1H), 3.96-4.10 (m, 2H), 3.89-3.96 (m, 1H),3.39-3.56 (m, 2H), 2.06 (s, 3H).

Example 67(S)-4-(4-fluoro-3-(3-(methyl(pyridin-3-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-67) Step 1: Preparation of(S)-4-(4-fluoro-3-(3-((pyridin-3-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 60(Step 1). Thus,(S)-4-(3-(3-aminopyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 2)(100 mg, 0.23 mmol) was reacted with nicotinaldehyde (26 uL,0.23 mmol) and sodium triacetoxyborohydride (114 mg, 0.54 mmol) toafford the intermediate compound(S)-4-(4-fluoro-3-(3-((pyridin-3-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one(86 mg, 82%).

Step 2: Preparation of(S)-4-(4-fluoro-3-(3-(methyl(pyridin-3-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 60(Step 2). Thus, this intermediate compound (Step 1)(86 mg, 0.19 mmol)was reacted with K₂CO₃ (52 mg, 0.38 mmol) and iodomethane (24 uL, 0.38mmol) to afford the title compound (98 mg, 91%).

¹H-NMR (MeOD, 400 MHz): δ 10.36 (s, 0.4H), 10.01 (s, 0.6H), 8.46 (m,3H), 7.73 (m, 3H), 7.40 (m, 1H), 7.38 (m, 3H), 7.04 (m, 1H), 4.27 (s,2H), 3.89 (m, 1H), 3.67 (m, 3H), 3.47 (m, 3H), 3.12 (m, 1H), 2.13 (m,5H), 1.87 (m, 1H).

Example 68(R)-4-(4-fluoro-3-(3-(methyl(pyridin-3-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-68) Step 1: Preparation of(R)-4-(4-fluoro-3-(3-((pyridin-3-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 60(Step 1). Thus,(R)-4-(3-(3-aminopyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 1)(100 mg, 0.23 mmol) was reacted with nicotinaldehyde (26 uL,0.23 mmol) and sodium triacetoxyborohydride (114 mg, 0.54 mmol) toafford the intermediate compound(R)-4-(4-fluoro-3-(3-((pyridin-3-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one(86 mg, 82%).

Step 2: Preparation of(R)-4-(4-fluoro-3-(3-(methyl(pyridin-3-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 60(Step 2). Thus, this intermediate compound (Step 1)(86 mg, 0.19 mmol)was reacted with K₂CO₃ (52 mg, 0.38 mmol) and iodomethane (24 uL, 0.38mmol) to afford the title compound (98 mg, 91%).

¹H-NMR (MeOD, 400 MHz): δ 10.36 (s, 0.4H), 10.01 (s, 0.6H), 8.46 (m,3H), 7.73 (m, 3H), 7.40 (m, 1H), 7.38 (m, 3H), 7.04 (m, 1H), 4.27 (s,2H), 3.89 (m, 1H), 3.67 (m, 3H), 3.47 (m, 3H), 3.12 (m, 1H), 2.13 (m,3H), 1.87 (m, 1H).

Example 694-(3-(3-(cyclopropyl(methyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-69) Step 1: Preparation of4-(3-(3-(cyclopropylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 60(Step 1). Thus,4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(100 mg, 0.23 mmol) was reacted with(1-ethoxycyclopropoxy)trimethylsilane(46 uL, 0.23 mmol) and sodiumtriacetoxyborohydride (114 mg, 0.54 mmol) to afford the intermediatecompound4-(3-(3-(cyclopropylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(58 mg, 71%).

Step 2: Preparation of4-(3-(3-(cyclopropyl(methyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 60(Step 2). Thus, this intermediate compound (Step 1)(58 mg, 0.16 mmol)was reacted with K₂CO₃ (44 mg, 0.32 mmol) and iodomethane (33 uL, 0.32mmol) to afford the title compound (62 mg, 95%).

¹H-NMR (MeOD, 400 MHz): δ 8.32-8.39 (d, 1H), 7.89-7.95 (d, 1H),7.78-7.88 (m, 2H), 7.46-7.53 (m, 1H), 7.39-7.45 (m, 1H), 7.14 (t, 1H),4.37 (s, 2H), 4.14-4.22 (m, 1H), 4.05-4.13 (m, 2H), 3.98-4.03 (m, 2H),3.54-3.63 (m, 1H), 2.26 (s, 3H), 0.34-0.56 (m, 4H).

Example 704-(3-(3-(cyclopropyl(ethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-70) Step 1: Preparation of4-(3-(3-(cyclopropylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 60(Step 1) to afford the intermediate compound4-(3-(3-(cyclopropylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(58 mg, 71%).

Step 2: Preparation of4-(3-(3-(cyclopropyl(ethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 60(Step 2). Thus, this intermediate compound (Step 1)(58 mg, 0.16 mmol)was reacted with K₂CO₃ (44 mg, 0.32 mmol) and iodoethane (33 uL, 0.32mmol) to afford the title compound (58 mg, 91%).

¹H-NMR (MeOD, 400 MHz): δ 8.32-8.40 (m, 1H), 7.90-7.95 (m, 1H),7.77-7.89 (m, 2H), 7.46-7.54 (m, 1H), 7.30-7.45 (m, 1H), 7.14 (t, 1H),4.36 (s, 2H), 3.95-4.24 (m, 4H), 3.73-3.84 (m, 1H), 2.60-2.71 (m, 2H),1.68-1.78 (m, 1H), 1.19-1.26 (m, 1H), 1.01-1.10 (m, 3H), 0.35-0.58 (m,4H).

Example 714-(3-(3-(cyclobutyl(methyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-71) Step 1: Preparation of4-(3-(3-(cyclobutylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 60(Step 1). Thus,4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(100 mg, 0.23 mmol) was reacted with cyclobutanone (17 uL,0.23 mmol) and sodium triacetoxyborohydride (114 mg, 0.54 mmol) toafford the intermediate compound4-(3-(3-(cyclobutylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(84 mg, 90%).

Step 2: Preparation of4-(3-(3-(cyclobutyl(methyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 60(Step 2). Thus, this intermediate compound (Step 1)(84 mg, 0.21 mmol)was reacted with K₂CO₃ (57 mg, 0.41 mmol) and iodomethane (25 uL, 0.41mmol) to afford the title compound (82 mg, 93%).

¹H-NMR (MeOD, 400 MHz): δ 8.36 (d, 1H), 7.93 (d, 1H), 7.79-7.89 (m, 2H),7.48-7.54 (m, 1H), 7.42 (d, 1H), 7.15 (t, 1H), 4.37 (s, 2H), 4.08-4.18(m, 1H), 3.98-4.04 (m, 1H), 3.89-3.99 (m, 2H), 3.35-3.43 (m, 1H),2.80-2.90 (m, 1H), 2.06 (s, 3H), 1.81-1.97 (m, 4H), 1.59-1.72 (m, 2H).

Example 724-(3-(3-(cyclopentyl(prop-2-yn-1-yl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-72) Step 1: Preparation of4-(3-(3-(cyclopentylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 60(Step 1). Thus,4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(100 mg, 0.23 mmol) was reacted with cyclopentanone (20 uL,0.23 mmol) and sodium triacetoxyborohydride (114 mg, 0.54 mmol) toafford the intermediate compound4-(3-(3-(cyclopentylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(74 mg, 77%).

Step 2: Preparation of4-(3-(3-(cyclopentyl(prop-2-yn-1-yl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 60(Step 2). Thus, this intermediate compound (Step 1)(74 mg, 0.18 mmol)was reacted with K₂CO₃ (49 mg, 0.35 mmol) and 1N solution of propargylbromide in toluene (0.35 mL, 0.35 mmol) to afford the title compound (67mg, 81%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.32 (s, 1H), 8.48-8.46 (m, 1H), 7.80-7.71(m, 3H), 7.51-7.48 (m, 1H), 7.33-7.29 (m, 1H), 7.01 (t, 1H), 4.29-4.25(m, 3H), 4.12-3.99 (m, 3H), 3.81-3.74 (m, 1H), 3.52-3.39 (m, 2H),2.96-2.89 (m, 1H), 2.16 (m, 1H), 1.83-1.51 (m, 6H), 1.41-1.30 (m, 2H)

Example 734-(3-(3-(3,3-difluoropyrrolidin-1-yl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-73) Step 1: Preparation of4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

4-(4-fluoro-3-(3-hydroxyazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one(example 6)(200 mg, 0.57 mmol) was dissolved in dichloromethane (2.5 mL)and 1,4-dioxane (1 mL). Dess-Mart in periodinane (DMP, 484 mg, 1.14mmol) was added at 0° C., after stirring at room temperature for 12 h.The reaction mixture added dichloromethane and washed with aqueoussodium hydroxide and water. The combined organic layers were dried overMgSO₄, filtered, evaporated in vacuum to afford the intermediatecompound4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one(162 mg, 81%).

Step 2: Preparation of4-(3-(3-(3,3-difluoropyrrolidin-1-yl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

3,3-difluoropyrrolidine (43 uL, 0.46 mmol) was added to a solution ofthe intermediate compound (Step 1)(162 mg, 0.46 mmol) in1,2-dichloroethane/methanol (2 mL/1 mL) and stirred for 30 min thenacetic acid (31 uL, 0.54 mmol) and sodium triacetoxyborohydride (227 mg,1.07 mmol) was added to the reaction mixture at 0° C. and stirred for 12hours. The reaction mixture was concentrated in vacuum, added 2NNaOH(aq) and extracted into dichloromethane. The combined organic layerswere dried over MgSO₄, filtered, evaporated in vacuum and purified usingsilica chromatography to afford the title compound (134 mg, 66%).

¹H-NMR (DMSO, 400 MHz): δ 12.62 (s, 1H), 8.26 (d, 1H), 7.99 (d, 1H),7.90 (t, 1H), 7.84 (t, 1H), 7.45 (d, 2H), 7.23 (t, 1H), 4.33 (s, 2H),4.11 (m, 1H), 4.07-0.03 (m, 1H), 3.96 (t, 1H), 3.89-3.85 (m, 1H),3.81-3.78 (m, 1H), 2.90 (t, 2H), 2.69-2.65 (m, 2H), 2.30-2.19 (m, 2H).

Example 74

4-(4-fluoro-3-(3-(4-fluoropiperidin-1-yl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-74)

Step 1: Preparation of4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 1) to afford the intermediate compound4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81mg, 162%).

Step 2: Preparation of4-(4-fluoro-3-(3-(4-fluoropiperidin-1-yl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 2). Thus, this intermediate compound (Step 1)(162 mg, 0.46 mmol)was reacted with 4-fluoropiperidine (43 uL, 0.46 mmol) and sodiumtriacetoxyborohydride (227 mg, 1.07 mmol) to afford the title compound(145 mg, 72%).

¹H-NMR (DMSO, 400 MHz): δ 12.61 (s, 1H), 8.26 (d, 1H), 7.99 (d, 1H),7.89 (t, 1H), 7.83 (t, 1H), 7.48-7.42 (m, 2H), 7.22 (t, 1H), 4.78-4.60(m, 1H), 4.33 (s, 2H), 4.05-4.01 (m, 1H), 3.91 (t, 1H), 3.81-3.77 (m,1H), 3.74-3.70 (m, 1H), 2.41-2.31 (m, 2H), 2.25-2.12 (m, 2H), 1.91-1.77(m, 2H), 1.75-1.64 (m, 2H).

Example 754-(3-([1,3′-biazetidine]-1′-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-75) Step 1: Preparation of4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 1) to afford the intermediate compound4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81mg, 162%).

Step 2: Preparation of4-(3-([1,3′-biazetidine]-1′-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 2). Thus, this intermediate compound (Step 1)(162 mg, 0.46 mmol)was reacted with azetidine (28 uL, 0.46 mmol) and sodiumtriacetoxyborohydride (227 mg, 1.07 mmol) to afford the title compound(113 mg, 74%).

¹H-NMR (DMSO, 400 MHz): δ 12.61 (s, 1H), 8.26 (d, 1H), 7.78 (d, 1H),7.89 (t, 1H), 7.83 (t, 1H), 7.45 (m, 2H), 7.22 (t, 1H), 4.33 (d, 2H),4.11 (m, 1H), 3.97 (t, 1H), 3.87 (t, 1H), 3.68 (m, 1H), 3.60 (t, 1H),3.10 (m, 4H), 1.95 (t, 2H).

Example 764-(4-fluoro-3-(3-(pyrrolidin-1-yl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-76) Step 1: Preparation of4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 1) to afford the intermediate compound4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81mg, 162%).

Step 2: Preparation of4-(4-fluoro-3-(3-(pyrrolidin-1-yl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 2). Thus, this intermediate compound (Step 1)(162 mg, 0.46 mmol)was reacted with pyrrolidine (38 uL, 0.46 mmol) and sodiumtriacetoxyborohydride (227 mg, 1.07 mmol) to afford the title compound(159 mg, 85%).

¹H-NMR (MeOD, 400 MHz): δ 8.37-8.35 (m, 1H), 7.94 (d, 1H), 7.98 (d, 1H),7.92-7.82 (m, 2H), 7.48-7.42 (m, 2H), 7.22 (t, 1H), 4.34 (s, 2H),4.07-4.03 (m, 1H), 3.94 (t, 1H), 3.85-3.81 (m, 1H), 3.76-3.73 (m, 1H),3.27-3.23 (m, 1H), 2.38 (d, 4H), 1.69 (s, 4H).

Example 774-(4-fluoro-3-(3-(piperidin-1-yl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-77) Step 1: Preparation of4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 1) to afford the intermediate compound4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81mg, 162%).

Step 2: Preparation of4-(4-fluoro-3-(3-(piperidin-1-yl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 2). Thus, this intermediate compound (Step 1)(162 mg, 0.46 mmol)was reacted with piperidine (43 uL, 0.46 mmol) and sodiumtriacetoxyborohydride (227 mg, 1.07 mmol) to afford the title compound(162 mg, 85%).

¹H-NMR (DMSO, 400 MHz): δ 12.62 (s, 1H), 8.25 (d, 1H), 8.01 (d, 1H),7.88 (t, 1H), 7.82 (t, 1H), 7.48-7.39 (m, 2H), 7.21 (t, 1H), 4.33 (s,2H), 4.10-4.08 (m, 1H), 3.95 (t, 1H), 3.85 (t, 1H), 3.69-3.65 (m, 1H),3.61-3.55 (m, 1H), 2.42 (t, 4H), 1.55-1.49 (m, 6H).

Example 784-(4-fluoro-3-(3-(4-methylpiperazin-1-yl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-78) Step 1: Preparation of4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 1) to afford the intermediate compound4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81mg, 162%).

Step 2: Preparation of4-(4-fluoro-3-(3-(4-methylpiperazin-1-yl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 2). Thus, this intermediate compound (Step 1)(162 mg, 0.46 mmol)was reacted with 1-methylpiperazine (50 uL, 0.46 mmol) and sodiumtriacetoxyborohydride (227 mg, 1.07 mmol) to afford the title compound(90 mg, 45%).

¹H-NMR (MeOD, 400 MHz): δ 8.37-8.35 (m, 1H), 7.95-7.93 (m, 1H),7.89-7.81 (m, 2H), 7.57-7.40 (m, 2H), 7.15 (t, 1H), 4.38 (s, 2H),4.21-4.02 (m, 2H), 3.97-3.82 (m, 2H), 3.65 (m, 1H), 2.94-2.80 (m, 6H),2.59 (s, 3H).

Example 794-(4-fluoro-3-(3-(phenylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-79) Step 1: Preparation of4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 1) to afford the intermediate compound4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81mg, 162%).

Step 2: Preparation of4-(4-fluoro-3-(3-(phenylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 2). Thus, this intermediate compound (Step 1)(162 mg, 0.46 mmol)was reacted with aniline (42 uL, 0.46 mmol), titanium(IV) epoxide(Ti[OCH₂(CH₃)₄], 96 mL, 46 mmol) and sodium triacetoxyborohydride (227mg, 1.0 mmol) to afford the title compound (43 mg, 22%).

¹H-NMR (DMSO, 400 MHz): δ 12.60 (s, 1H), 8.25 (d, 1H), 7.97 (d, 1H),7.89 (t, 1H), 7.82 (t, 1H), 7.41 (m, 1H), 7.33 (m, 1H), 7.23 (t, 1H),7.06 (t, 2H), 6.59 (d, 2H), 6.51 (t, 1H), 4.38 (m, 1H), 4.33 (s, 2H),4.28-4.19 (m, 2H), 3.80 (dd, 1H), 3.70 (m, 1H).

Example 804-(4-fluoro-3-(3-((1-(trifluoromethyl)cyclopropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-80) Step 1: Preparation of4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 1) to afford the intermediate compound4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81mg, 162%).

Step 2: Preparation of4-(4-fluoro-3-(3-((1-(trifluoromethyl)cyclopropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 2). Thus, this intermediate compound (Step 1)(162 mg, 0.46 mmol)was reacted with 1-(trifluoromethyl)cyclopropylamine (74 mg, 0.46 mmol)and sodium triacetoxyborohydride (227 mg, 1.07 mmol) to afford the titlecompound (51 mg, 24%).

¹H-NMR (MeOD, 400 MHz): δ 8.25 (d, 1H), 7.83 (d, 1H), 7.71-7.76 (m, 2H),7.33-7.39 (m, 1H), 7.31-7.40 (m, 1H), 7.03 (t, 1H), 4.25 (s, 2H),4.20-4.26 (m, 1H), 4.01-4.06 (m, 1H), 3.66-3.80 (m, 3H), 0.97-0.99 (m,2H), 0.81-0.83 (m, 2H).

Example 814-(4-fluoro-3-(3-(prop-2-yn-1-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-81) Step 1: Preparation of4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 1) to afford the intermediate compound4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81mg, 162%).

Step 2: Preparation of4-(4-fluoro-3-(3-(prop-2-yn-1-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 2). Thus, this intermediate compound (Step 1)(162 mg, 0.46 mmol)was reacted with propargylamine (29 uL, 0.46 mmol) and sodiumtriacetoxyborohydride (227 mg, 1.07 mmol) to afford the title compound(134 mg, 66%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.40 (s, 1H), 8.48-8.46 (m, 1H), 7.79-7.71(m, 3H), 7.52-7.50 (m, 1H), 7.32-7.30 (m, 1H), 7.02 (t, 1H), 4.43-4.38(m, 1H), 4.28 (s, 2H), 4.23-4.20 (m, 1H), 4.00-3.93 (m, 1H), 3.88-3.85(m, 2H), 3.42 (q, 2H), 2.21 (m, 1H).

Example 82(S)-4-(4-fluoro-3-(3-((1-methoxypropan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-82) Step 1: Preparation of4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 1) to afford the intermediate compound4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81mg, 162%).

Step 2: Preparation of(S)-4-(4-fluoro-3-(3-((1-methoxypropan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 2). Thus, this intermediate compound (Step 1)(162 mg, 0.46 mmol)was reacted with (S)-1-methoxypropane-2-amine (48 uL, 0.46 mmol) andsodium triacetoxyborohydride (227 mg, 1.07 mmol) to afford the titlecompound (125 mg, 64%).

¹H-NMR (MeOD, 400 MHz): δ 8.38-8.35 (m, 1H), 7.95-7.93 (m, 1H),7.89-7.82 (m, 2H), 7.52-7.50 (m, 1H), 7.45-7.43 (m, 1H), 7.14 (t, 1H),4.38 (s, 2H), 4.12-4.10 (m, 1H), 4.18-4.15 (m, 1H), 3.84-3.77 (m, 3H),3.22-3.19 (m, 1H), 2.89-2.87 (m, 1H), 2.03 (s, 3H), 1.00 (t, 3H).

Example 83(R)-4-(4-fluoro-3-(3-((1-ethoxypropan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-83) Step 1: Preparation of4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 1) to afford the intermediate compound4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81mg, 162%).

Step 2: Preparation of(R)-4-(4-fluoro-3-(3-((1-methoxypropan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 2). Thus, this intermediate compound (Step 1)(162 mg, 0.46 mmol)was reacted with (R)-1-methoxypropane-2-amine (48 uL, 0.4 mmol) andsodium triacetoxyborohydride (227 mg, 1.07 mmol) to afford the titlecompound (125 mg, 64%).

¹H-NMR (MeOD, 400 MHz): δ 8.38-8.35 (m, 1H), 7.95-7.93 (m, 1H),7.89-7.82 (m, 2H), 7.52-7.50 (m, 1H), 7.45-7.43 (m, 1H), 7.14 (t, 1H),4.38 (s, 2H), 4.12-4.10 (m, 1H), 4.18-4.15 (m, 1H), 3.84-3.77 (m, 3H),3.22-3.19 (m, 1H), 2.89-2.87 (m, 1H), 2.03 (s, 3H), 1.00 (t, 3H).

Example 844-(4-fluoro-3-(3-((1-(hydroxymethyl)cyclopropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-84) Step 1: Preparation of4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 1) to afford the intermediate compound4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81mg, 162%).

Step 2: Preparation of4-(4-fluoro-3-(3-((1-(hydroxymethyl)cyclopropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 2). Thus, this intermediate compound (Step 1)(162 mg, 0.46 mmol)was reacted with (1-aminocyclopropyl)methanol (40 mg, 0.46 mmol) andsodium triacetoxyborohydride (227 mg, 1.07 mmol) to afford the titlecompound (84 mg, 43%).

¹H-NMR (MeOD, 400 MHz): δ 8.35-8.34 (m, 1H), 7.95-7.82 (m, 3H),7.51-7.44 (m, 2H), 7.13 (t, 1H), 4.37-4.33 (m, 3H), 4.19-4.17 (m, 1H),3.90-3.86 (m, 3H), 1.29-1.27 (m, 1H), 0.57-0.54 (m, 2H), 0.52-0.50 (m,2H).

Example 854-(4-fluoro-3-(3-((1-methylcyclopropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-85) Step 1: Preparation of4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 1) to afford the intermediate compound4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81mg, 162%).

Step 2: Preparation of4-(4-fluoro-3-(3-((1-methylcyclopropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 2). Thus, this intermediate compound (Step 1)(162 mg, 0.46 mmol)was reacted with 1-methylcyclopropanamine (43 uL, 0.46 mmol) and sodiumtriacetoxyborohydride (227 mg, 1.07 mmol) to afford the title compound(35 mg, 19%).

¹H-NMR (MeOD, 400 MHz): δ 8.36 (d, 1H), 7.93 (d, 1H), 7.80-7.86 (m, 2H),7.42-7.52 (m, 2H), 7.14 (t, 1H), 4.32-4.37 (m, 3H), 4.16 (t, 1H),3.78-3.88 (m, 3H), 1.29 (s, 3H), 0.51-0.57 (m, 2H, 0.33-0.39 (m, 2H).

Example 86(R)-4-(3-(3-((3,3-dimethylbutan-2-yl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-86) Step 1: Preparation of4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 1) to afford the intermediate compound4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81mg, 162%).

Step 2: Preparation of(R)-4-(3-(3-((3,3-dimethylbutan-2-yl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 2). Thus, this intermediate compound (Step 1)(162 mg, 0.46 mmol)was reacted with (R)-3,3-dimethylbutan-2-amine (55 uL, 0.46 mmol) andsodium triacetoxyborohydride (227 mg, 1.07 mmol) to afford the titlecompound (110 mg, 55%).

¹H-NMR (MeOD, 400 MHz): δ 8.39 (d, 1H), 7.87-8.38 (m, 3H), 7.43-7.53 (m,2H), 7.17 (t, 1H), 4.41 (s, 2H), 4.28-4.40 (m, 1H), 4.09-4.18 (m, 1H),3.71-3.90 (m, 3H), 2.17-2.27 (m, 1H), 0.94-0.98 (m, 12H).

Example 87(S)-4-(3-(3-((3,3-dimethylbutan-2-yl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-87) Step 1: Preparation of4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 1) to afford the intermediate compound4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81mg, 162%).

Step 2: Preparation of(S)-4-(3-(3-((3,3-dimethylbutan-2-yl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 2). Thus, this intermediate compound (Step 1)(162 mg, 0.46 mmol)was reacted with (S)-3,3-dimethylbutan-2-amine (55 uL, 0.46 mmol) andsodium triacetoxyborohydride (227 mg, 1.07 mmol) to afford the titlecompound (110 mg, 55%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.28 (d, 1H), 8.48-8.46 (m, 1H), 7.79-7.70(m, 3H), 7.50 (d, 1H), 7.32-7.28 (m, 1H), 7.01 (t, 1H), 4.43-4.32 (m,1H), 4.27 (s, 2H), 4.21-4.09 (m, 1H), 3.84-3.70 (m, 3H), 2.26-2.14 (m,1H), 0.96-0.90 (m, 3H), 0.88-0.86 (dd, 9H).

Example 88(R)-4-(4-fluoro-3-(3-((3-ethylbutan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-88) Step 1: Preparation of4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 1) to afford the intermediate compound4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81mg, 162%).

Step 2: Preparation of(R)-4-(4-fluoro-3-(3-((3-methylbutan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 2). Thus, this intermediate compound (Step 1)(162 mg, 0.46 mmol)was reacted with (R)-3-methylbutan-2-amine (53 uL, 0.46 mmol) and sodiumtriacetoxyborohydride (227 mg, 1.07 mmol) to afford the title compound(113 mg, 58%).

¹H-NMR (MeOD, 400 MHz): δ 8.39 (d, 1H), 7.83-8.38 (m, 3H), 7.44-7.52 (m,2H), 7.17 (t, 1H), 4.63 (brs, 2H), 4.40 (s, 2H), 3.76-3.86 (m, 3H),2.44-2.46 (m, 1H), 1.64-1.67 (m, 1H), 0.86-0.96 (m, 9H).

Example 89(S)-4-(4-fluoro-3-(3-((3-methylbutan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-89) Step 1: Preparation of4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 1) to afford the intermediate compound4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81mg, 162%).

Step 2: Preparation of(S)-4-(4-fluoro-3-(3-((3-methylbutan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 2). Thus, this intermediate compound (Step 1)(162 mg, 0.46 mmol)was reacted with (S)-3-methylbutan-2-amine (53 uL, 0.46 mmol) and sodiumtriacetoxyborohydride (227 mg, 1.07 mmol) to afford the title compound(113 mg, 58%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.61 (s, 1H), 8.48-8.46 (m, 1H), 7.80-7.71(m, 3H), 7.53-7.47 (m, 1H), 7.32-7.30 (m, 1H), 7.01 (t, 1H), 4.38 (m,1H), 4.28 (s, 2H), 4.15 (m, 1H), 3.84-3.71 (m, 3H), 2.45 (m, 1H), 1.59(m, 1H), 0.94-0.83 (m, 9H).

Example 904-(4-fluoro-3-(3-((1-(methoxymethyl)cyclopropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-90) Step 1: Preparation of4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 1) to afford the intermediate compound4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81mg, 162%).

Step 2: Preparation of4-(4-fluoro-3-(3-((1-(methoxymethyl)cyclopropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 2). Thus, the intermediate compound (Step 1)(162 mg, 0.46 mmol)was reacted with 1-(methoxymethyl)cyclopropanamine (46 mg, 0.46 mmol),and sodium triacetoxyborohydride (227 mg, 1.07 mmol) to afford the titlecompound (78 mg, 39%)

¹H-NMR (MeOD, 400 MHz): δ 8.37-8.35 (m, 1H), 7.95-7.93 (m, 1H),7.89-7.82 (m, 2H), 7.50-7.43 (m, 2H), 7.16-7.13 (m, 1H), 4.37 (s, 2H),7.36-7.33 (m, 1H), 7.15-7.14 (m, 1H), 3.87-3.82 (m, 3H), 3.31 (s, 3H),1.29 (br, 2H), 0.60-0.59 (m, 2H), 0.53-0.51 (m, 2H).

Example 914-(3-(3-(but-3-yn-1-ylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-91) Step 1: Preparation of4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 1) to afford the intermediate compound4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81mg, 162%).

Step 2: Preparation of4-(3-(3-(but-3-yn-1-ylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 2). Thus, the intermediate compound (Step 1)(162 mg, 0.46 mmol)was reacted with but-3-yn-1-amine (38 uL, 0.46 mmol), and sodiumtriacetoxyborohydride (227 mg, 1.07 mmol) to afford the title compound(145 mg, 78%).

¹H-NMR (MeOD, 400 MHz): δ 8.38-8.35 (m, 1H), 7.94-7.82 (m, 3H),7.52-7.43 (m, 2H), 7.17-7.14 (m, 1H), 4.37 (s, 2H), 4.32-4.29 (m, 1H),4.15-4.13 (m, 1H), 3.88-3.69 (m, 3H), 2.69-2.66 (m, 2H), 2.34-2.31 (m,3H).

Example 924-(4-fluoro-3-(3-((2-ethylallyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-92) Step 1: Preparation of4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 1) to afford the intermediate compound4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81mg, 162%).

Step 2: Preparation of4-(4-fluoro-3-(3-((2-methylallyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 2). Thus, the intermediate compound (Step 1)(162 mg, 0.46 mmol)was reacted with 2-methylprop-2-en-1-amine (35 uL, 0.46 mmol), andsodium triacetoxyborohydride (227 mg, 1.07 mmol) to afford the titlecompound (83 mg, 45%).

¹H-NMR (MeOD, 400 MHz): δ 8.38 (d, 1H), 8.36 (d, 1H), 7.81-7.95 (m, 2H),7.44-7.50 (m, 1H), 7.11-7.17 (m, 1H), 4.38 (brs, 2H), 4.26-4.30 (m, 1H),4.11-4.13 (m, 1H), 3.85-3.88 (m, 1H), 3.76-3.78 (m, 1H), 3.66-3.69 (m,1H), 3.34 (s, 2H), 3.08 (s, 2H), 1.25 (s, 3H).

Example 934-(4-fluoro-3-(3-((3-hydroxy-2,2-dimethylpropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-93) Step 1: Preparation of4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 1) to afford the intermediate compound4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81mg, 162%).

Step 2: Preparation of4-(4-fluoro-3-(3-((3-hydroxy-2,2-dimethylpropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 2). Thus, the intermediate compound (Step 1)(162 mg, 0.46 mmol)was reacted with 3-amino-2,2-dimethylpropan-1-ol (47 mg, 0.46 mmol), andsodium triacetoxyborohydride (227 mg, 1.07 mmol) to afford the titlecompound (24 mg, 12%).

¹H-NMR (CDCl₃, 400 MHz): δ 11.53 (br, 1H), 8.46 (m, 1H), 7.78-7.72 (m,3H), 7.51-7.49 (m, 1H), 7.34-7.29 (m, 1H), 7.01 (t, 1H), 4.36-4.32 (m,3H), 4.18-4.10 (m, 1H), 3.90-3.78 (m, 2H), 3.67 (m, 1H), 2.53-2.45 (m,5H), 0.93 (s, 3H), 0.91 (s, 3H).

Example 941-(((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)ethyl)benzoyl)azetidin-3-yl)amino)methyl)cyclopropanecarbonitrile;(I-94) Step 1: Preparation of4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 1) to afford the intermediate compound4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81mg, 162%).

Step 2: Preparation of1-(((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)methyl)cyclopropanecarbonitrile

This compound was made using the procedure described for example 73(Step 2). Thus, the intermediate compound (Step 1)(162 mg, 0.46 mmol)was reacted with 1-(aminomethyl)cyclopropanecarbonitrile (44 mg, 0.46mmol), and sodium triacetoxyborohydride (227 mg, 1.07 mmol) to affordthe title compound (91 mg, 46%).

¹H-NMR (MeOD, 400 MHz): δ 8.38 (dd, 1H), 8.00 (d, 1H), 7.83-7.92 (m,2H), 7.54-7.62 (m, 2H), 7.14 (t, 1H), 4.41 (s, 2H), 4.28-4.36 (m, 1H),4.14-4.18 (m, 1H), 3.71-3.81 (m, 3H), 1.35 (s, 4H).

Example 95 4-(4-fluoro-3-(3-((2,2,2-trifluoroethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-95) Step 1: Preparation of4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 1) to afford the intermediate compound4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81mg, 162%).

Step 2: Preparation of4-(4-fluoro-3-(3-((2,2,2-trifluoroethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 2). Thus, the intermediate compound (Step 1)(162 mg, 0.46 mmol)was reacted with 2,2,2-trifluoroethaneamine (36 uL, 0.46 mmol), andsodium triacetoxyborohydride (227 mg, 1.07 mmol) to afford the titlecompound (200 mg, 60%).

¹H-NMR (MeOD, 400 MHz): δ 8.38-8.35 (m, 1H), 7.95-7.92 (m, 1H),7.89-7.82 (m, 2H), 7.52-7.50 (m, 1H), 7.45-7.43 (m, 1H), 7.17-7.12 (m,1H), 4.37 (s, 2H), 4.30-4.28 (m, 1H), 4.16-4.14 (m, 1H), 3.86-3.83 (m,1H), 3.78-3.76 (m, 1H), 3.68-3.66 (m, 1H), 2.90-2.83 (m, 2H).

Example 96(R)-4-(4-fluoro-3-(3-(pyrrolidin-3-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-96) Step 1: Preparation of4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 1) to afford the intermediate compound4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81mg, 162%).

Step 2: Preparation of(R)-tert-butyl-3-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidine-3-yl)amino)pyrrolidin-1-carboxylate

The intermediate compound (Step 1, 162 mg, 0.46 mmol) was added to asolution of (R)-tert-butyl-3-aminopyrrolidin-1-carboxylate (25 uL, 0.46mmol) in dichloromethane (3 mL), methanol (1 mL) and stirred for 30 minthen acetic acid (36 uL, 0.69 mmol) and sodium triacetoxyborohydride(144 mg, 0.69 mmol) was added to the reaction mixture at 0° C. andstirred for 12 hours. The reaction mixture was concentrated in vacuo,added 2N NaOH(aq) and extracted into dichloromethane. The combinedorganic layers were dried over MgSO₄, filtered, evaporated in vacuo andpurified using silica chromatography to afford(R)-tert-butyl-3-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidine-3-yl)amino)pyrrolidin-1-carboxylate(122 mg, 43%).

Step 3: Preparation of(R)-4-(4-fluoro-3-(3-(pyrrolidin-3-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

The intermediate compound (Step 2)(122 mg, 0.20 mmol) in dichloromethane(4 mL) cooled to 0° C. was added 1.0 N HCl solution (0.40 mL, 0.40mmol), and the mixture was stirred at room temperature for 3 h. Thereact ion mixture was concentrated in vacuo, added dichloromethane andwashed with 2N NaOH(aq) and water. The combined organic layers weredried over MgSO₄, filtered, evaporated in vacuo and purified usingsilica chromatography to afford the title compound (76 mg, 90%).

¹H-NMR (MeOD, 400 MHz): δ 8.38-8.36 (m, 1H), 7.95-7.83 (m, 3H), 7.54 (m,1H), 7.44-7.42 (m, 1H), 7.25 (t, 1H), 4.38 (s, 2H), 4.35-4.33 (m, 1H),4.19-4.17 (m, 1H), 3.78-3.77 (m, 1H), 3.74-3.71 (m, 2H), 3.36-3.21 (m,2H), 3.17-3.08 (m, 2H), 2.09-1.99 (m, 1H), 1.82-1.79 (m, 1H), 1.28 (s,1H).

Example 97(S)-4-(4-fluoro-3-(3-(pyrrolidin-3-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-97) Step 1: Preparation of4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 73(Step 1) to afford the intermediate compound4-(4-fluoro-3-(3-oxoazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (81mg, 162%).

Step 2: Preparation of(S)-tert-butyl-3-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidine-3-yl)amino)pyrrolidin-1-carboxylate

This compound was made using the procedure described for example 96(Step 2). Thus, the intermediate compound (Step 1)(162 mg, 0.46 mmol)was reacted with (S)-tertbutyl-3-aminopyrrolidin-1-carboxylate (25 uL,0.46 mmol), and sodium triacetoxyborohydride (144 mg, 0.69 mmol) toafford the title compound (122 mg, 43%).

Step 3: Preparation of(S)-4-(4-fluoro-3-(3-(pyrrolidin-3-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 96(Step 3). Thus, the intermediate compound (Step 2)(122 mg, 0.20 mmol)was reacted with 1.0 N HCl solution (0.40 mL, 0.40 mmol)) to afford thetitle compound (76 mg, 90%).

¹H-NMR (MeOD, 400 MHz): δ 8.38-8.36 (m, 1H), 7.95-7.83 (m, 3H), 7.54 (m,1H), 7.44-7.42 (m, 1H), 7.25 (t, 1H), 4.38 (s, 2H), 4.35-4.33 (m, 1H),4.19-4.17 (m, 1H), 3.78-3.77 (m, 1H), 3.74-3.71 (m, 2H), 3.36-3.21 (m,2H), 3.17-3.08 (m, 2H), 2.09-1.99 (m, 1H), 1.82-1.79 (m, 1H), 1.28 (s,1H).

Example 981-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)ethyl)benzoyl)azetidin-3-yl)amino)cyclopentanecarbonitrile;(I-98) Step 1: Preparation of1-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)cyclopentanecarbonitrile

Cyclopentanone (79 uL, 1.17 mmol) was added to a solution of4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(200 mg, 1.17 mmol) in 1,2-dichloroethane (6 mL) and stirred for 30 minthen acetic acid (67 uL, 1.17 mmol) and trimethylsilyl cyanide (0.30 mL,2.34 mmol) was added to the reaction mixture at 0° C. and stirred for 12hours. The reaction mixture was concentrated in vacuo, added 2N NaOH(aq)and extracted into dichloromethane. The combined organic layers weredried over MgSO₄, filtered, evaporated in vacuo and purified usingsilica chromatography to afford the title compound (328 mg, 63%).

¹H-NMR (MeOD, 400 MHz): δ 8.36 (m, 1H), 7.93-7.79 (m, 3H), 7.51-7.43 (m,2H), 7.14 (t, 1H), 4.43-4.39 (m, 1H), 4.36 (s, 2H), 4.25 (m, 1H),3.96-3.91 (m, 3H), 2.10-2.02 (m, 2H), 1.86-1.76 (m, 6H).

Example 991-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)ethyl)benzoyl)azetidin-3-yl)amino)cyclobutanecarbonitrile;(I-99) Step 1: Preparation of1-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)cyclobutanecarbonitrile

This compound was made using the procedure described for example 98(Step 1). Thus,4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(200 mg, 1.17 mmol) was reacted with cyclobutanone (87 uL,1.17 mmol), trimethylsilyl cyanide (0.30 mL, 2.34 mmol) to afford thetitle compound (293 mg, 58%).

¹H-NMR (MeOD, 400 MHz): δ 8.35 (m, 1H), 7.92-7.78 (m, 3H), 7.50-7.43 (m,2H), 7.13 (t, 1H), 4.41-4.39 (m, 1H), 4.36 (s, 2H), 4.23 (m, 1H),3.98-3.92 (m, 2H), 3.85-3.78 (m, 1H), 2.48-2.41 (m, 2H), 2.20-2.02 (m,2H).

Example 1002-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)propanenitrile;(I-100) Step 1: Preparation of2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)propanenitrile

This compound was made using the procedure described for example 98(Step 1). Thus,4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(200 mg, 1.17 mmol) was reacted with acetaldehyde (70 uL,1.17 mmol), trimethylsilyl cyanide (0.30 mL, 2.34 mmol) to afford thetitle compound (336 mg, 71%).

¹H-NMR (MeOD, 400 MHz): δ 8.36 (m, 1H), 7.94-7.79 (m, 3H), 7.50-7.44 (m,2H), 7.14 (t, 1H), 4.41-4.17 (m, 4H), 4.00-3.93 (m, 1H), 3.89-3.66 (m,3H), 1.42 (d, 3H).

Example 1012-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)butanenitrile;(I-101) Step 1: Preparation of2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)butanenitrile

This compound was made using the procedure described for example 98(Step 1). Thus,4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3, 200 mg, 1.17 mmol) was reacted with propionaldehyde (84 uL,1.17 mmol), trimethylsilyl cyanide (0.30 mL, 2.34 mmol) to afford thetitle compound (294 mg, 60%).

¹H-NMR (MeOD, 400 MHz): δ 8.35 (m, 1H), 7.94-7.80 (m, 3H), 7.49-7.44 (m,2H), 7.14 (t, 1H), 4.40-4.16 (m, 4H), 4.00-3.91 (m, 1H), 3.88-3.76 (m,2H), 3.61-3.50 (m, 1H), 1.79-1.68 (m, 2H), 1.08-1.01 (m, 3H).

Example 1022-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)-3-ethylbutanenitrile;(I-102) Step 1: Preparation of2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)-3-methylbutanenitrile

This compound was made using the procedure described for example 98(Step 1). Thus,4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(200 mg, 1.17 mmol) was reacted with isobutylaldehyde (0.1mL, 1.17 mmol), trimethylsilyl cyanide (0.30 mL, 2.34 mmol) to affordthe title compound (294 mg, 58%).

¹H-NMR (MeOD, 400 MHz): δ 8.34 (m, 1H), 7.92-7.78 (m, 3H), 7.49-7.44 (m,2H), 7.13 (t, 1H), 4.39-4.15 (m, 4H), 4.02-3.96 (m, 1H), 3.88-3.76 (m,2H), 3.46-3.39 (dd, 1H), 1.93 (m, 1H), 1.04-0.87 (m, 6H).

Example 1032-cyclopropyl-2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)acetonitrile;(I-103) Step 1: Preparation of2-cyclopropyl-2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)acetonitrile

This compound was made using the procedure described for example 98(Step 1). Thus,4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(200 mg, 1.17 mmol) was reacted with cyclopropancabaldehyde(79 uL, 1.17 mmol), trimethylsilyl cyanide (0.30 mL, 2.34 mmol) toafford the title compound (409 mg, 81%).

¹H-NMR (MeOD, 400 MHz): δ 8.35 (m, 1H), 7.93-7.78 (m, 3H), 7.50-7.44 (m,2H), 7.13 (t, 1H), 4.40-4.17 (m, 4H), 4.01-3.79 (m, 3H), 3.42-3.37 (dd,1H), 1.17 (m, 1H), 0.65-0.42 (m, 4H).

Example 1044-(4-fluoro-3-(3-((1-(trifluoromethyl)cyclobutyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-104) Step 1: Preparation of4-(4-fluoro-3-(3-((1-(trifluoromethyl)cyclobutyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 98(Step 1). Thus,4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 3)(200 mg, 1.17 mmol) was reacted with cyclobutanone (79 uL,1.17 mmol), trifluoromethyltrimethylsilane (0.30 mL, 2.34 mmol) toafford the title compound (328 mg, 63%).

¹H-NMR (MeOD, 400 MHz): δ 8.26 (d, 1H), 7.72-7.84 (m, 3H), 7.34-7.41 (m,2H), 7.04 (t, 1H), 7.71-7.76 (m, 2H), 7.33-7.39 (m, 1H), 7.31-7.40 (m,1H), 7.03 (t, 1H), 4.25 (s, 2H), 4.20-4.26 (m, 1H), 4.01-4.06 (m, 1H),3.66-3.80 (m, 3H), 0.97-0.99 (m, 2H), 0.81-0.83 (m, 2H).

Example 105(S)-4-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-105) Step 1: Preparation of(S)-4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)benzaldehyde

This compound was made using the procedure described for example 11(Step 1). Thus, (S)—N-methyl-N-(pyrrolidin-3-yl)pyrimidine-2-amine (200mg, 1.12 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (188 mg,1.12 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU, 553 mg, 1.46 mmol), N,N-diisopropylethylamine (DIPEA, 0.40 mL, 2.24 mmol) to afford(S)-4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)benzaldehyde(154 mg, 43%).

Step 2: Preparation of(S,Z)-3-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one

This compound was made using the procedure described for example 11(Step 2). Thus, the intermediate compound (Step 1)(154 mg, 0.47 mmol)was reacted withdimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (114 mg, 0.47mmol), triethylamine (98 uL, 0.47 mmol) to afford intermediate compound(S,Z)-3-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one(107 mg, 51%).

Step 3: Preparation of(S)-4-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one)

This compound was made using the procedure described for example 11(Step 3). Thus, the intermediate compound (Step 2)(107 mg, 0.24 mmol)was reacted with hydrazine monohydrate (23 uL, 0.48 mmol) to affordtitle compound (55 mg, 50%).

¹H-NMR (CDCl₃, 400 MHz): δ 9.96 (d, 1H), 8.45 (m, 1H), 8.43 (dd, 2H),7.75 (m, 3H), 7.39 (m, 1H), 7.31 (m, 1H), 7.02 (m, 1H), 6.52 (q, 1H),5.53 (m, 1H), 4.26 (d, 2H), 3.93 (m, 1H), 3.66 (m, 1H), 3.44 (m, 1H),3.27 (m, 1H), 3.10 (s, 1.3H), 3.04 (s, 1.7H), 2.21 (m, 1H), 2.06 (m,1H).

Example 106(S)-4-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-106) Step 1: Preparation of(S)-4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)benzaldehyde

This compound was made using the procedure described for example 11(Step 1). Thus, (S)—N-ethyl-N-(pyrrolidin-3-yl)pyrimidine-2-amine (200mg, 1.12 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (175 mg,1.04 mmol), O-(benzotriazole-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate (HBTU, 512 mg, 1.35 mmol), N,N-diisopropylethylamine (DIPEA, 0.36 mL, 2.08 mmol) to afford(S)-4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)benzaldehyde(149 mg, 42%).

Step 2: Preparation of(S,Z)-3-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one

This compound was made using the procedure described for example 11(Step 2). Thus, intermediate compound (Step 1)(149 mg, 0.43 mmol) wasdimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphate (105 mg, 0.43mmol), triethylamine (92 uL, 0.66 mmol) to afford(S,Z)-3-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one(102 mg, 51%).

Step 3: Preparation of(S)-4-(3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 11(Step 3). Thus, the intermediate compound (Step 2)(102 mg, 0.22 mmol)was reacted with hydrazine monohydrate (21 uL, 0.45 mmol) to affordtitle compound (53 mg, 50%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.63 (d, 1H), 8.49 (m, 1H), 8.32 (dd, 2H),7.73 (m, 3H), 7.39 (m, 1H), 7.28 (m, 1H), 7.02 (m, 1H), 6.50 (m, 1H),5.13 (dt, 1H), 4.29 (d, 2H), 3.95 (m, 1H), 3.58 (m, 2H), 3.46 (m, 2H),3.27 (m, 1H), 2.23 (m, 1H), 2.09 (m, 1H), 1.93 (dt, 3H).

Example 1074-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-107) Step 1: Preparation of4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)benzaldehyde

This compound was made using the procedure described for example 11(Step 1). Thus, N-(azetidin-3-yl)-N-methylpyrimidine-2-amine (200 mg,1.12 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (204 mg, 1.22mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU, HBTU, 600 mg, 1.58 mmol), N,N-diisopropylethylamine (DIPEA, 0.42 mL, 2.44 mmol) to afford4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)benzaldehyde(149 mg, 42%).

Step 2: Preparation of(Z)-3-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one

This compound was made using the procedure described for example 11(Step 2). Thus, the intermediate compound (Step 1)(202 mg, 0.65 mmol)was reacted withdimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (156 mg, 0.65mmol), triethylamine (0.13 mL, 0.96 mmol) to afford intermediatecompound(Z)-3-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one(169 mg, 61%).

Step 3: Preparation of4-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 11(Step 3). Thus, the intermediate compound (Step 2)(169 mg, 0.39 mmol)was reacted with hydrazine monohydrate (38 uL, 0.79 mmol) to affordtitle compound (89 mg, 51%).

¹H-NMR (CDCl₃, 400 MHz): δ 8.53 (dd, 1H), 8.31 (d, 2H), 7.80-7.70 (m,3H), 7.54 (dd, 1H), 7.34-7.30 (m, 1H), 7.10-7.03 (m, 1H), 6.55 (t, 1H),5.48-5.41 (m, 1H), 4.52-4.45 (m, 1H), 4.39-4.27 (m, 4H), 4.23-4.12 (m,1H), 3.21 (s, 3H).

Example 1084-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-108) Step 1: Preparation of4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)benzaldehyde

This compound was made using the procedure described for example 11(Step 1). Thus, N-(azetidin-3-yl)-N-ethylpyrimidine-2-amine (200 mg,1.12 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (188 mg, 1.12mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU, 553 mg, 1.45 mmol), N,N-diisopropylethylamine (DIPEA, 0.39 mL, 2.24 mmol) to afford4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)benzaldehyde(195 mg, 53%).

Step 2: Preparation of (Z)-3-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one

This compound was made using the procedure described for example 11(Step 2). Thus, the intermediate compound (Step 1)(195 mg, 0.59 mmol)was reacted withdimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (144 mg, 0.59mmol), triethylamine (0.12 mL, 0.89 mmol) to afford intermediatecompound(Z)-3-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one (161 mg, 61%).

Step 3: Preparation of4-(4-fluoro-3-(3-(methyl(pyrimidin-2-_(y)l)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 11(Step 3). Thus, the intermediate compound (Step 2)(161 mg, 0.36 mmol)was reacted with hydrazine monohydrate (36 uL, 0.73 mmol) to affordtitle compound (84 mg, 51%).

¹H-NMR (CDCl₃, 400 MHz): δ 8.53 (dd, 1H), 8.31 (d, 2H), 7.80-7.70 (m,3H), 7.54 (dd, 1H), 7.34-7.30 (m, 1H), 7.10-7.03 (m, 1H), 6.55 (t, 1H),5.09-5.01 (m, 1H), 4.55-4.46 (m, 1H), 4.44-4.28 (m, 4H), 4.20-4.13 (m,1H), 3.82-3.63 (m, 2H), 1.18 (t, 3H).

Example 109 4-(4-fluoro-3-(3-(pyrimidin-2-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-109) Step 1:Preparation of4-fluoro-3-(3-(pyrimidin-2-ylamino)azetidine-1-carbonyl)benzaldehyde

This compound was made using the procedure described for example 11(Step 1). Thus, N-(azetidin-3-yl)-pyrimidine-2-amine (220 mg, 1.46 mmol)was reacted with 2-fluoro-5-formylbenzoic acid (246 mg, 1.46 mmol),O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU, 722 mg, 1.90 mmol), N,N-diisopropyl ethylamine (DIPEA, 0.51 mL,2.93 mmol) to afford4-fluoro-3-(3-(pyrimidin-2-ylamino)azetidine-1-carbonyl)benzaldehyde(233 mg, 53%).

Step 2: Preparation of(Z)-3-(4-fluoro-3-(3-(pyrimidin-2-ylamino)azetidine-1-carbonyl)benzylidene)isofuran-1(3H)-one

This compound was made using the procedure described for example 11(Step 2). Thus, the intermediate compound (Step 1)(233 mg, 0.78 mmol)was reacted withdimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (188 mg, 0.78mmol), triethylamine (0.16 mL, 1.16 mmol) to afford intermediatecompound(Z)-3-(4-fluoro-3-(3-(pyrimidin-2-ylamino)azetidine-1-carbonyl)benzylidene)isofuran-1(3H)-one(197 mg, 61%).

Step 3: Preparation of4-(4-fluoro-3-(3-(pyrimidin-2-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 11(Step 3). Thus, the intermediate compound (Step 2)(197 mg, 0.47 mmol)was reacted with hydrazine monohydrate (46 uL, 0.95 mmol) to affordtitle compound (104 mg, 51%).

¹H-NMR (DMSO, 400 MHz): δ 7.45 (d, 2H), 7.41 (d, 1H), 7.14 (d, 1H),7.06-6.96 (m, 3H), 6.63-6.62 (m, 2H), 6.40-6.35 (m, 1H), 5.80 (t, 1H),3.78-3.70 (m, 1H), 3.49-3.44 (m, 3H), 3.40-3.36 (m, 1H), 3.12-3.08 (m,1H), 3.05-3.01 (m, 1H).

Example 110(S)-4-(4-fluoro-3-(3-(pyrimidin-2-ylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-110) Step 1: Preparation of(S)-4-fluoro-3-(3-(pyrimidin-2-ylamino)pyrrolidine-1-carbonyl)benzaldehyde

This compound was made using the procedure described for example 11(Step 1). Thus, (S)—N-(pyrrolidin-3-yl)pyrimidine-2-amine (300 mg, 1.82mmol) was reacted with 2-fluoro-5-formylbenzoic acid (307 mg, 1.82mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU, 900 mg, 2.38 mmol), N,N-diisopropylethylamine (DIPEA, 0.64 mL, 3.65 mmol) to afford(S)-4-fluoro-3-(3-(pyrimidin-2-ylamino)pyrrolidine-1-carbonyl)benzaldehyde(252 mg, 44%).

Step 2: Preparation of(S,Z)-3-(4-fluoro-3-(3-(pyrimidin-2-ylamino)pyrrolidine-1-carbonyl)benzylidene)isofuran-1(3H)-one

This compound was made using the procedure described for example 11(Step 2). Thus, the intermediate compound (Step 1)(252 mg, 0.80 mmol)was reacted withdimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (195 mg, 0.80mmol), triethylamine (0.17 mL, 1.20 mmol) to afford intermediatecompound(S,Z)-3-(4-fluoro-3-(3-(pyrimidin-2-ylamino)pyrrolidine-1-carbonyl)benzylidene)isofuran-1(3H)-one(138 mg, 40%).

Step 3: Preparation of(S)-4-(4-fluoro-3-(3-(pyrimidin-2-ylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 11(Step 3). Thus, the intermediate compound (Step 2)(138 mg, 0.32 mmol)was reacted with hydrazine monohydrate (32 uL, 0.65 mmol) to affordtitle compound (73 mg, 51%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.74 (d, 1H), 8.46 (m, 1H), 8.32 (dd, 2H),7.73 (m, 3H), 7.40 (m, 1H), 7.28 (m, 1H), 7.01 (q, 1H), 6.60 (m, 1H),5.60 (m, 1H), 4.60 (m, 1H), 4.27 (d, 2H), 4.03 (dd, 0.4H), 3.84 (m,0.6H), 3.73 (m, 1H), 3.49 (m, 1H), 3.41 (m, 1H), 3.25 (m, 1H), 2.28 (m,1H), 1.95 (m, 1H).

Example 111(S)-4-(3-(3-((6-chloropyridazin-3-yl)(methyl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-111) Step 1: Preparation of(S)-3-(3-((6-chloropyridazin-3-yl)(methyl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde

This compound was made using the procedure described for example 11(Step 1). Thus,(S)-6-chloro-N-methyl-N-(pyrrolidin-3-yl)pyridazin-3-amine (120 mg, 0.71mmol) was reacted with 2-fluoro-5-formylbenzoic acid (118 mg, 0.71mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU, 348 mg, 0.91 mmol), N,N-diisopropylethylamine (DIPEA, 0.25 mL, 1.41 mmol) to afford(S)-3-(3-((6-chloropyridazin-3-yl)(methyl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde(115 mg, 45%).

Step 2: Preparation of(S,Z)-3-(3-(3-((6-chloropyridazin-3-yl)(methyl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzylidene)isofuran-1(3H)-one

This compound was made using the procedure described for example 11(Step 2). Thus, the intermediate compound (Step 1)(115 mg, 0.31 mmol)was reacted withdimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (77 mg, 0.31mmol), triethylamine (66 uL, 0.48 mmol) to afford intermediate compound(S,Z)-3-(3-(3-((6-chloropyridazin-3-yl)(methyl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzylidene)isofuran-1(3H)-one(85 mg, 56%).

Step 3: Preparation of(S)-4-(3-(3-((6-chloropyridazin-3-yl)(methyl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 11(Step 3). Thus, the intermediate compound (Step 2)(85 mg, 0.18 mmol) wasreacted with hydrazine monohydrate (17 uL, 0.36 mmol) to afford titlecompound (46 mg, 52%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.68 (d, 1H), 8.45 (m, 1H), 7.76 (m, 3H),7.37 (m, 1H), 7.28 (m, 1H), 6.83 (d, 1H), 7.05 (q, 1H), 6.83 (q, 1H),5.57 (m, 0.4H), 5.39 (m, 0.6H), 4.29 (d, 2H), 3.92 (m, 1H), 3.66 (m,2H), 3.50 (m, 1H), 3.26 (m, 1H), 2.91 (s, 1.5H), 2.96 (s, 1.5H), 2.24(m, 2H).

Example 112(S)-4-(3-(3-((6-chloropyridazin-3-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-112) Step 1: Preparation of(S)-3-(3-((6-chloropyridazin-3-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde

This compound was made using the procedure described for example 11(Step 1). Thus, (S)-6-chloro-N-(pyrrolidin-3-yl)pyridazin-3-amine (200mg, 1.01 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (169 mg,1.01 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU, 496 mg, 1.31 mmol), N,N-diisopropylethylamine (DIPEA, 0.35 mL, 2.01 mmol) to afford(S)-3-(3-((6-chloropyridazin-3-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde(158 mg, 45%).

Step 2: Preparation of(S,Z)-3-(3-(3-((6-chloropyridazin-3-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzylidene) isofuran-1(3H)-one

This compound was made using the procedure described for example 11(Step 2). Thus, the intermediate compound (Step 1)(158 mg, 0.45 mmol)was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (109 mg, 0.45 mmol), triethylamine (95 uL,0.68 mmol) to afford intermediate compound(S,Z)-3-(3-(3-((6-chloropyridazin-3-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzylidene)isofuran-1(3H)-one(117 mg, 56%).

Step 3: Preparation of(S)-4-(3-(3-((6-chloropyridazin-3-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 11(Step 3). Thus, the intermediate compound (Step 2)(117 mg, 0.25 mmol)was reacted with hydrazine monohydrate (25 uL, 0.50 mmol) to affordtitle compound (64 mg, 52%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.83 (d, 1H), 8.41 (m, 1H), 7.72 (m, 3H),7.35 (m, 1H), 7.02 (m, 2H), 6.67 (dd, 1H), 5.37 (m, 1H), 4.57 (m, 1H),4.27 (dd, 2H), 3.77 (m, 1H), 3.43 (m, 2H), 3.23 (m, 2H), 2.02 (m, 1H).

Example 113(S)-4-(4-fluoro-3-(3-(methyl(pyridazin-3-yl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-113) Step 1: Preparation of(S)-4-fluoro-3-(3-(methyl(pyridazin-3-yl)amino)pyrrolidine-1-carbonyl)benzaldehyde

This compound was made using the procedure described for example 11(Step 1). Thus, (S)—N-methyl-N-(pyrrolidin-3-yl)pyridazin-3-amine (200mg, 1.22 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (204 mg,1.22 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU, 600 mg, 1.58 mmol), N,N-diisopropylethylamine (DIPEA, 0.42 mL, 2.43 mmol) to afford(S)-4-fluoro-3-(3-(methyl(pyridazin-3-yl)amino)pyrrolidine-1-carbonyl)benzaldehyde(172 mg, 45%).

Step 2: Preparation of(S,Z)-3-(4-fluoro-3-(3-(methyl(pyridazin-3-yl)amino)pyrrolidine-1-carbonyl)benzylidene)isofuran-1(3H)-one

This compound was made using the procedure described for example 11(Step 2). Thus, the intermediate compound (Step 1)(172 mg, 0.55 mmol)was reacted withdimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (132 mg, 0.55mmol), triethylamine (0.12 mL, 0.55 mmol) to afford intermediatecompound(S,Z)-3-(4-fluoro-3-(3-(methyl(pyridazin-3-yl)amino)pyrrolidine-1-carbonyl)benzylidene)isofuran-1(3H)-one(132 mg, 56%).

Step 3: Preparation of(S)-4-(4-fluoro-3-(3-(methyl(pyridazin-3-yl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 11(Step 3). Thus, the intermediate compound (Step 2)(132 mg, 0.31 mmol)was reacted with hydrazine monohydrate (30 uL, 0.61 mmol) to affordtitle compound (71 mg, 52%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.68 (d, 1H), 8.6 (m, 1H), 8.45 (m, 1H),7.75 (m, 3H), 7.37 (m, 2H), 7.20 (m, 1H), 7.04 (m, 1H), 6.67 (dd, 1H),4.65 (m, 2H), 4.27 (d, 2H), 3.91 (m, 2H), 3.48 (m, 1H), 3.22 (m, 1H),2.40 (m, 1H), 2.02 (m, 1H).

Example 1144-(3-(3-((6-chloropyridazin-3-yl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2)-one;(I-114) Step 1: Preparation of3-(3-((6-chloropyridazin-3-yl)amino)azetidine-1-carbonyl)-4-fluorobenzaldehyde

This compound was made using the procedure described for example 11(Step 1). Thus, N-(azetidin-3-yl)-6-chloropyridazin-3-amine (200 mg,1.08 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (182 mg, 1.08mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU, 534 mg, 1.40 mmol), N,N-diisopropylethylamine (DIPEA, 0.38 mL, 2.17 mmol) to afford3-(3-((6-chloropyridazin-3-yl)amino)azetidine-1-carbonyl)-4-fluorobenzaldehyde(184 mg, 51%).

Step 2: Preparation of(Z)-3-(3-(3-((6-chloropyridazin-3-yl)amino)azetidine-1-carbonyl)-4-fluorobenzylidene)isofuran-1(3H)-one

This compound was made using the procedure described for example 11(Step 2). Thus, the intermediate compound (Step 1)(184 mg, 0.55 mmol)was reacted withdimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (133 mg, 0.55mmol), triethylamine (0.12 mL, 0.83 mmol) to afford intermediatecompound(Z)-3-(3-(3-((6-chloropyridazin-3-yl)amino)azetidine-1-carbonyl)-4-fluorobenzylidene)isofuran-1(3H)-one (146 mg, 59%).

Step 3: Preparation of4-(3-(3-((6-chloropyridazin-3-yl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 11(Step 3). Thus, the intermediate compound (Step 2)(146 mg, 0.33 mmol)was reacted with hydrazine monohydrate (32 uL, 0.66 mmol) to affordtitle compound (82 mg, 54%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.16 (s, 1H), 8.47-8.42 (m, 1H), 7.79-7.67(m, 4H), 7.47 (dd, 1H), 7.35-7.31 (m, 1H), 7.18 (d, 1H), 7.04-6.99 (m,1H), 6.72 (d, 1H), 5.29-5.25 (m, 1H), 4.87-4.73 (m, 1H), 4.65-4.59 (m,1H), 4.47-4.43 (m, 1H), 4.31-4.26 (m, 3H), 4.09-4.05 (m, 1H), 3.92-3.88(m, 1H).

Example 1154-(3-(3-((6-chloropyridazin-3-yl)(ethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-115) Step 1: Preparation of3-(3-((6-chloropyridazin-3-yl)(methyl)amino)azetidine-1-carbonyl)-4-fluorobenzaldehyde

This compound was made using the procedure described for example 11(Step 1). Thus, N-(azetidin-3-yl)-6-chloro-N-methylpyridazin-3-amine(200 mg, 1.00 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (169mg, 1.00 mmol), 0-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU, 496 mg, 1.31 mmol), N,N-diisopropylethylamine (DIPEA, 0.35 mL, 2.01 mmol) to afford3-(3-((6-chloropyridazin-3-yl)(methyl)amino)azetidine-1-carbonyl)-4-fluorobenzaldehyde(179 mg, 51%).

Step 2: Preparation of(Z)-3-(3-(3-((6-chloropyridazin-3-yl)(methyl)amino)azetidine-1-carbonyl)-4-fluorobenzylidene)isofuran-1(3H)-one

This compound was made using the procedure described for example 11(Step 2). Thus, the intermediate compound (Step 1)(179 mg, 0.51 mmol)was reacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (124 mg, 0.51 mmol), triethylamine (0.11mL, 0.77 mmol) to afford intermediate compound(Z)-3-(3-(3-((6-chloropyridazin-3-yl)(methyl)amino)azetidine-1-carbonyl)-4-fluorobenzylidene)isofuran-1(3H)-one(140 mg, 59%).

Step 3: Preparation of4-(3-(3-((6-chloropyridazin-3-yl)(methyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 11(Step 3). Thus, the intermediate compound (Step 2)(140 mg, 0.30 mmol)was reacted with hydrazine monohydrate (30 uL, 0.60 mmol) to affordtitle compound (78 mg, 54%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.16 (s, 1H), 8.47-8.42 (m, 1H), 7.79-7.67(m, 4H), 7.47 (dd, 1H), 7.35-7.31 (m, 1H), 7.18 (d, 1H), 7.04-6.99 (m,1H), 6.72 (d, 1H), 5.21-5.15 (m, 1H), 4.87-4.73 (m, 1H), 4.65-4.59 (m,1H), 4.47-4.43 (m, 1H), 4.31-4.26 (m, 3H), 4.09-4.05 (m, 1H), 3.92-3.88(m, 1H), 3.06 (s, 3H).

Example 1164-(3-(3-(cyclobutyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-116) Step 1: Preparation of3-(3-(cyclobutyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)-4-fluorobenzaldehyde

This compound was made using the procedure described for example 11(Step 1). Thus, N-(azetidin-3-yl)-N-cyclobutylpyrimidine-2-amine (500mg, 2.44 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (411 mg,2.44 mmol), 0-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU, 1.2 g, 3.18 mmol), N,N-diisopropyl ethylamine(DIPEA, 0.86 mL, 4.89 mmol) to afford3-(3-(cyclobutyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)-4-fluorobenzaldehyde(442 mg, 51%).

Step 2: Preparation of(Z)-3-(3-(3-(cyclobutyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)-4-fluorobenzylidene)isofuran-1(3H)-one

This compound was made using the procedure described for example 11(Step 2). Thus, the intermediate compound (Step 1)(442 mg, 1.24 mmol)was reacted withdimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (302 mg, 1.24mmol), triethylamine (0.26 mL, 1.87 mmol) to afford intermediatecompound(Z)-3-(3-(3-(cyclobutyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)-4-fluorobenzylidene)isofuran-1(3H)-one(288 mg, 49%).

Step 3: Preparation of4-(3-(3-(cyclobutyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 11(Step 3). Thus, the intermediate compound (Step 2)(288 mg, 0.62 mmol)was reacted with hydrazine monohydrate (60 uL, 1.22 mmol) to affordtitle compound (124 mg, 42%).

¹H-NMR (CDCl₃, 400 MHz): δ 8.46-8.44 (m, 1H), 8.28 (d, 2H), 7.75-7.72(m, 3H), 7.52-7.49 (m, 1H), 7.36-7.28 (m, 1H), 7.04-6.99 (m, 1H), 6.55(t, 1H), 4.97-4.90 (m, 1H), 4.82-4.74 (m, 1H), 4.66-4.62 (m, 1H),4.47-4.43 (m, 1H), 4.31-4.26 (m, 3H), 4.17-4.13 (m, 1H), 2.25-2.01 (m,5H).

Example 1174-(4-fluoro-3-(3-(pyridazin-3-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-117) Step 1: Preparation of4-fluoro-3-(3-(pyridazin-3-ylamino)azetidine-1-carbonyl)benzaldehyde

This compound was made using the procedure described for example 11(Step 1). Thus, N-(azetidin-3-yl)pyridazin-3-amine (200 mg, 1.33 mmol)was reacted with 2-fluoro-5-formylbenzoic acid (224 mg, 1.33 mmol),0-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU, 656 mg, 1.73 mmol), N,N-diisopropyl ethylamine (DIPEA, 0.46 mL,2.66 mmol) to afford4-fluoro-3-(3-(pyridazin-3-ylamino)azetidine-1-carbonyl)benzaldehyde(203 mg, 51%).

Step 2: Preparation of(Z)-3-(4-fluoro-3-(3-(pyridazin-3-ylamino)azetidine-1-carbonyl)benzylidene)isofuran-1(3H)-one

This compound was made using the procedure described for example 11(Step 2). Thus, the intermediate compound (Step 1)(203 mg, 0.68 mmol)was reacted withdimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (164 mg, 0.68mmol), triethylamine (0.14 mL, 1.02 mmol) to afford intermediatecompound(Z)-3-(4-fluoro-3-(3-(pyridazin-3-ylamino)azetidine-1-carbonyl)benzylidene)isofuran-1(3H)-one(172 mg, 61%).

Step 3: Preparation of4-(4-fluoro-3-(3-(pyridazin-3-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 11(Step 3). Thus, the intermediate compound (Step 2)(172 mg, 0.41 mmol)was reacted with hydrazine monohydrate (40 uL, 0.82 mmol) to affordtitle compound (93 mg, 52%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.86 (s, 1H), 8.58-8.57 (m, 1H), 8.44 (d,1H), 7.78-7.69 (m, 3H), 7.48-7.46 (m, 1H), 7.35-7.31 (m, 1H), 7.18-7.15(m, 1H), 7.00 (t, 1H), 6.70 (d, 1H), 5.68 (brs, 1H), 4.81-4.74 (m, 1H),4.61-4.42 (m, 2H), 4.26 (s, 2H), 4.11-4.07 (m, 1H), 3.93-3.90 (m, 1H).

Example 118(R)-4-(3-(3-((6-chloropyridazin-3-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-118) Step 1: Preparation of(R)-3-(3-((6-chloropyridazin-3-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde

This compound was made using the procedure described for example 11(Step 1). Thus, (R)-6-chloro-N-(pyrrolidin-3-yl)pyridazin-3-amine (200mg, 1.00 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (169 mg,1.00 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU, 496 mg, 1.31 mmol), N,N-diisopropylethylamine (DIPEA, 0.35 mL, 2.01 mmol) to afford(R)-3-(3-((6-chloropyridazin-3-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde(179 mg, 51%).

Step 2: Preparation of(R,Z)-3-(3-(3-((6-chloropyridazin-3-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzylidene)isofuran-1(3H)-one

This compound was made using the procedure described for example 11(Step 2). Thus, the intermediate compound (Step 1)(179 mg, 0.51 mmol)was reacted withdimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (124 mg, 0.51mmol), triethylamine (0.1 mL, 0.77 mmol) to afford intermediate compound(R,Z)-3-(3-(3-((6-chloropyridazin-3-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzylidene)isofuran-1(3H)-one(146 mg, 61%).

Step 3: Preparation of(R)-4-(3-(3-((6-chloropyridazin-3-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 11(Step 3). Thus, the intermediate compound (Step 2)(146 mg, 0.31 mmol)was reacted with hydrazine monohydrate (30 uL, 0.31 mmol) to affordtitle compound (78 mg, 52%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.85 (s, 0.6H), 10.61 (s, 0.4H), 8.43 (m,1H), 7.79-7.66 (m, 3.5H), 7.32 (m, 1.5H), 7.15-6.98 (m, 2H), 6.69 (d,0.4H), 6.58 (d, 0.6H), 5.37 (t, 1H), 4.65 (m, 0.4H), 4.58 (m, 0.6H),4.26 (d, 2H), 3.99-3.83 (m, 1H), 3.79-3.66 (m, 2H), 3.43 (m, 0.5H), 3.25(dd, 0.5H), 2.32 (m, 1H), 2.04 (m, 1H).

Example 119(R)-4-(3-(3-((6-chloropyridazin-3-yl)(methyl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-119) Step 1: Preparation of(R)-3-(3-((6-chloropyridazin-3-yl)(methyl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde

This compound was made using the procedure described for example 11(Step 1). Thus,(R)-6-chloro-N-methyl-N-(pyrrolidin-3-yl)pyridazin-3-amine (200 mg, 0.94mmol) was reacted with 2-fluoro-5-formylbenzoic acid (158 mg, 0.94mmol), 0-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU, 463 mg, 1.22 mmol), N,N-diisopropylethylamine (DIPEA, 0.33 mL, 1.88 mmol) to afford(R)-3-(3-((6-chloropyridazin-3-yl)(methyl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde(174 mg, 51%).

Step 2: Preparation of(R,Z)-3-(3-(3-((6-chloropyridazin-3-yl)methyl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzylidene)isofuran-1(3H)-one

This compound was made using the procedure described for example 11(Step 2). Thus, the intermediate compound (Step 1)(174 mg, 0.48 mmol)was reacted withdimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (116 mg, 0.48mmol), triethylamine (0.1 mL, 0.72 mmol) to afford intermediate compound(R,Z)-3-(3-(3-((6-chloropyridazin-3-yl)methyl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzylidene)isofuran-1(3H)-one(140 mg, 61%).

Step 3: Preparation of(R)-4-(3-(3-((6-chloropyridazin-3-yl)(methyl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 11(Step 3). Thus, the intermediate compound (Step 2)(140 mg, 0.29 mmol)was reacted with hydrazine monohydrate (29 uL, 0.59 mmol) to affordtitle compound (74 mg, 52%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.42 (s, 0.6H), 10.29 (s, 0.4H), 8.46 (m,1H), 7.81-7.70 (m, 3H), 7.38 (m, 1H), 7.34-7.24 (m, 1H), 7.22 (d, 1H),7.03 (m, 1H), 6.82 (dd, 1H), 5.58 (m, 0.5H), 5.41 (m, 0.5H), 4.29 (s,0.8H), 4.28 (s, 1.2H), 3.92 (m, 1H), 3.74-3.61 (m, 2H), 3.44 (m, 0.5H),3.26 (dd, 0.5H), 2.99 (s, 1.2H), 2.94 (s, 1.8H), 2.32-2.04 (m, 2H).

Example 120(R)-4-(4-fluoro-3-(3-(pyrimidin-2-ylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-120) Step 1: Preparation of(R)-4-fluoro-3-(3-(pyrimidin-2-ylamino)pyrrolidine-1-carbonyl)benzaldehyde

This compound was made using the procedure described for example 11(Step 1). Thus, (R)—N-(pyrrolidin-3-yl)pyrimidine-2-amine (200 mg, 1.22mmol) was reacted with 2-fluoro-5-formylbenzoic acid (205 mg, 1.22mmol), 0-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU, 600 mg, 1.58 mmol), N,N-diisopropylethylamine (DIPEA, 0.42 mL, 2.44 mmol) to afford(R)-4-fluoro-3-(3-(pyrimidin-2-ylamino)pyrrolidine-1-carbonyl)benzaldehyde(195 mg, 51%).

Step 2: Preparation of(R,Z)-3-(4-fluoro-3-(3-(pyrimidin-2-ylamino)pyrrolidine-1-carbonyl)benzylidene)isofuran-1(3H)-one

This compound was made using the procedure described for example 11(Step 2). Thus, the intermediate compound (Step 1)(195 mg, 0.62 mmol)was reacted withdimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (150 mg, 0.62mmol), triethylamine (0.13 mL, 0.94 mmol) to afford intermediatecompound(R,Z)-3-(4-fluoro-3-(3-(pyrimidin-2-ylamino)pyrrolidine-1-carbonyl)benzylidene)isofuran-1(3H)-one (163 mg, 61%).

Step 3: Preparation of(R)-4-(4-fluoro-3-(3-(pyrimidin-2-ylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 11(Step 3). Thus, the intermediate compound (Step 2)(163 mg, 0.38 mmol)was reacted with hydrazine monohydrate (37 uL, 0.76 mmol) to affordtitle compound (88 mg, 52%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.73 (s, 0.6H), 10.51 (s, 0.4H), 8.42 (s,1H), 8.30 (dd, 2H), 7.78-7.68 (m, 3H), 7.41 (m, 1H), 7.28 (m, 1H), 7.03(q, 1H), 6.59 (m, 1H), 5.57 (dd, 1H), 4.63 (m, 0.4H), 4.53 (m, 0.6H),4.27 (s, 0.8H), 4.26 (s, 1.2H), 4.02 (dd, 0.4H), 3.88-3.68 (m, 1.6H),3.62 (dd, 0.4H), 3.52-3.40 (m, 1H), 3.26 (d, 0.6H), 2.37-2.24 (m, 1H),2.08-1.95 (m, 1H).

Example 121(R)-4-(3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-121) Step 1: Preparation of(R)-3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde

This compound was made using the procedure described for example 11(Step 1). Thus, (R)—N-ethyl-N-(pyrrolidin-3-yl)pyrimidine-2-amine (220mg, 1.14 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (158 mg,0.94 mmol), 0-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU, 564 mg, 1.49 mmol), N,N-diisopropylethylamine (DIPEA, 0.40 mL, 2.29 mmol) to afford(R)-3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde(200 mg, 51%).

Step 2: Preparation of(R,Z)-3-(3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzylidene)isofuran-1(3H)-one

This compound was made using the procedure described for example 11(Step 2). Thus, the intermediate compound (Step 1)(200 mg, 0.58 mmol)was reacted withdimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (141 mg, 0.58mmol), triethylamine (0.12 mL, 0.87 mmol) to afford intermediatecompound(R,Z)-3-(3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzylidene)isofuran-1(3H)-one(163 mg, 61%).

Step 3: Preparation of(R)-4-(3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 11(Step 3). Thus, the intermediate compound (Step 2)(163 mg, 0.36 mmol)was reacted with hydrazine monohydrate (34 uL, 0.72 mmol) to affordtitle compound (87 mg, 52%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.43 (s, 0.5H), 10.38 (s, 0.5H), 8.47 (m,1H), 8.30 (m, 2H), 7.81-7.68 (m, 3H), 7.39 (dd, 1H), 7.28 (m, 1H), 7.03(m, 1H), 6.51 (m, 1H), 5.37-5.18 (m, 1H), 4.29 (s, 0.8H), 4.27 (s,1.2H), 4.02-3.90 (m, 1H), 3.67-3.53 (m, 2H), 3.52-3.37 (m, 2.5H), 3.27(t, 0.5H), 2.22 (m, 1H), 2.13 (m, 1H), 1.22 (t, 1.5H), 1.16 (t, 1.5H).

Example 122(R)-4-(4-fluoro-3-(3-(pyridazin-3-ylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-122) Step 1: Preparation of(R)-4-fluoro-3-(3-(pyridazin-3-ylamino)pyrrolidine-1-carbonyl)benzaldehyde

This compound was made using the procedure described for example 11(Step 1). Thus, (R)—N-(pyrrolidin-3-yl)pyridazin-3-amine (200 mg, 1.34mmol) was reacted with 2-fluoro-5-formylbenzoic acid (225 mg, 1.34mmol), 0-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU, 660 mg, 1.74 mmol), N,N-diisopropylethylamine (DIPEA, 0.47 mL, 2.68 mmol) to afford(R)-4-fluoro-3-(3-(pyridazin-3-ylamino)pyrrolidine-1-carbonyl)benzaldehyde(214 mg, 51%).

Step 2: Preparation of(R,Z)-3-(4-fluoro-3-(3-(pyridazin-3-ylamino)pyrrolidine-1-carbonyl)benzylidene)isofuran-1(3H)-one

This compound was made using the procedure described for example 11(Step 2). Thus, the intermediate compound (Step 1)(214 mg, 0.68 mmol)was reacted withdimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (165 mg, 0.68mmol), triethylamine (0.14 mL, 1.02 mmol) to afford intermediatecompound(R,Z)-3-(4-fluoro-3-(3-(pyridazin-3-ylamino)pyrrolidine-1-carbonyl)benzylidene)isofuran-1(3H)-one (179 mg, 61%).

Step 3: Preparation of(R)-4-(4-fluoro-3-(3-(pyridazin-3-ylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 11(Step 3). Thus, the intermediate compound (Step 2)(179 mg, 0.42 mmol)was reacted with hydrazine monohydrate (41 uL, 0.84 mmol) to affordtitle compound (97 mg, 52%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.88 (s, 0.6H), 10.49 (s, 0.4H), 8.58 (m,1H), 8.44 (m, 1H), 7.74 (m, 3H), 7.39-7.25 (m, 2H), 7.17 (m, 1H), 7.02(m, 1H), 6.71 (d, 0.4H), 6.63 (d, 0.6H), 5.30 (m, 0.4H), 5.00 (m, 0.6H),4.28 (s, 0.8H), 4.26 (s, 1.2H), 4.02 (m, 0.6H), 3.87 (m, 1.4H),3.79-3.64 (m, 1H), 3.52-3.42 (m, 0.5H), 3.25 (m, 0.5H), 2.43-2.26 (m,1H), 2.07 (m, 1H).

Example 123(R)-4-(4-fluoro-3-(3-(methyl(pyridazin-3-yl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-123) Step 1: Preparation of(R)-4-fluoro-3-(3-(methyl(pyridazin-3-yl)amino)pyrrolidine-1-carbonyl)benzaldehyde

This compound was made using the procedure described for example 11(Step 1). Thus, (R)—N-methyl-N-(pyrrolidin-3-yl)pyridazin-3-amine (200mg, 1.12 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (188 mg,1.12 mmol), O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU, 553 mg, 1.46 mmol), N,N-diisopropylethylamine (DIPEA, 0.39 mL, 2.24 mmol) to afford(R)-4-fluoro-3-(3-(methyl(pyridazin-3-yl)amino)pyrrolidine-1-carbonyl)benzaldehyde(187 mg, 51%).

Step 2: Preparation of(R,Z)-3-(4-fluoro-3-(3-(methyl(pyridazin-3-yl)amino)pyrrolidine-1-carbonyl)benzylidene)isofuran-1(3H)-one

This compound was made using the procedure described for example 11(Step 2). Thus, the intermediate compound (Step 1)(187 mg, 0.57 mmol)was reacted withdimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (138 mg, 0.57mmol), triethylamine (0.12 mL, 0.86 mmol) to afford intermediatecompound(R,Z)-3-(4-fluoro-3-(3-(methyl(pyridazin-3-yl)amino)pyrrolidine-1-carbonyl)benzylidene)isofuran-1(3H)-one(155 mg, 61%).

Step 3: Preparation of(R)-4-(4-fluoro-3-(3-(methyl(pyridazin-3-yl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 11(Step 3). Thus, the intermediate compound (Step 2)(155 mg, 0.35 mmol)was reacted with hydrazine monohydrate (34 uL, 0.70 mmol) to affordtitle compound (83 mg, 52%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.70 (s, 0.6H), 10.25 (s, 0.4H), 8.61 (m,1H), 8.46 (m, 1H), 7.81-7.70 (m, 3H), 7.39 (m, 1H), 7.33-7.21 (m, 2H),7.08-6.97 (m, 1H), 6.81 (m, 1H), 5.74 (m, 0.4H), 5.52 (m, 0.6H), 4.29(s, 0.8H), 4.27 (s, 1.2H), 3.92 (m, 1H), 3.75-3.63 (m, 2H), 3.52-3.39(m, 0.4H), 3.24 (dd, 0.6H), 2.99 (s, 1.2H), 2.94 (s, 1.8H), 2.25 (m,1H), 2.08 (m, 1H).

Example 124(R)-4-(4-fluoro-3-(3-(thiazol-2-ylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-124) Step 1: Preparation of(R)-4-fluoro-3-(3-(thiazol-2-ylamino)pyrrolidine-1-carbonyl)benzaldehyde

This compound was made using the procedure described for example 11(Step 1). Thus, (R)—N-(pyrrolidine-3-yl)thiazol-2-amine (200 mg, 1.18mmol) was reacted with 2-fluoro-5-formylbenzoic acid (198 mg, 1.18mmol), 0-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU, 582 mg, 1.54 mmol), N,N-diisopropylethylamine (DIPEA, 0.42 mL, 2.36 mmol) to afford(R)-4-fluoro-3-(3-(thiazol-2-ylamino)pyrrolidine-1-carbonyl)benzaldehyde(170 m g, 45%).

Step 2: Preparation of(R,Z)-3-(4-fluoro-3-(3-(thiazol-2-ylamino)pyrrolidine-1-carbonyl)benzylidene)isofuran-1(3H)-one

This compound was made using the procedure described for example 11(Step 2). Thus, the intermediate compound (Step 1)(170 mg, 0.53 mmol)was reacted withdimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (128 mg, 0.53mmol), triethylamine (0.11 mL, 0.80 mmol) to afford intermediatecompound(R,Z)-3-(4-fluoro-3-(3-(thiazol-2-ylamino)pyrrolidine-1-carbonyl)benzylidene)isofuran-1(3H)-one (125 mg, 54%).

Step 3: Preparation of(R)-4-(4-fluoro-3-(3-(thiazol-2-ylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 11(Step 3). Thus, the intermediate compound (Step 2)(125 mg, 0.29 mmol)was reacted with hydrazine monohydrate (28 uL, 0.57 mmol) to affordtitle compound (67 mg, 52%).

¹H-NMR (MeOD, 400 MHz): δ 8.36 (m, 1H), 7.85 (m, 3H), 7.39 (m, 2H), 7.15(m, 1H), 6.96 (dd, 1H), 6.58 (dd, 1H), 4.41 (m, 2H), 3.71 (m, 3H), 3.40(m, 1H), 3.21 (m, 1H), 2.29 (m, 1H), 2.04 (m, 1H).

Example 125(R)-4-(3-(3-((5-ethynylpyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one; (I-125) Step 1: Preparation of(R)-3-(3-((5-ethynylpyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde

This compound was made using the procedure described for example 11(Step 1). Thus, (R)-5-ethynyl-N-(pyrrolidin-3-yl)pyrimidine-2-amine (230mg, 1.22 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (205 mg,1.22 mmol), 0-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU, 602 mg, 1.59 mmol), N,N-diisopropylethylamine (DIPEA, 0.43 mL, 2.44 mmol) to afford(R)-3-(3-((5-ethynylpyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde(210 mg, 51%).

Step 2: Preparation of(R,Z)-3-(3-(3-((5-ethynylpyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzylidene)isofuran-1(3H)-one

This compound was made using the procedure described for example 11(Step 2). Thus, the intermediate compound (Step 2)(210 mg, 0.62 mmol)was reacted withdimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (150 mg, 0.62mmol), triethylamine (0.13 mL, 0.93 mmol) to afford intermediatecompound(R,Z)-3-(3-(3-((5-ethynylpyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzylidene)isofuran-1(3H)-one(164 mg, 58%).

Step 3: Preparation of(R)-4-(3-(3-((5-ethynylpyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 11(Step 3). Thus, the intermediate compound (Step 2)(164 mg, 0.36 mmol)was reacted with hydrazine monohydrate (36 uL, 0.72 mmol) to affordtitle compound (103 mg, 61%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.10-0.93 (dd, 1H), 8.41-8.38 (m, 3H),7.78-7.68 (m, 3H), 7.41-7.37 (m, 1H), 7.32-7.27 (m, 1H), 7.04-7.02 (m,1H), 5.48-5.44 (m, 1H), 4.66-4.51 (m, 1H), 4.27 (s, 2H), 4.03 (m, 0.5H),3.85-3.39 (m, 3H), 3.28-3.26 (m, 0.5H), 3.19 (m, 2H), 2.40-2.23 (m, 1H),2.17-1.93 (m, 1H).

Example 126(R)-2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)ethyl)benzoyl)pyrrolidin-3-yl)amino)pyrimidine-5-carbonitrile; (I-126) Step 1: Preparation of(R)-2-((1-(2-fluoro-5-formylbenzoyl)pyrrolidin-3-yl)amino)pyrimidine-5-carbonitrile

This compound was made using the procedure described for example 11(Step 1). Thus, (R)-2-(pyrrolidin-3-ylamino)pyrimidine-5-carbonitrile(230 mg, 1.22 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (205mg, 1.22 mmol), 0-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU, 602 mg, 1.59 mmol), N,N-diisopropylethylamine (DIPEA, 0.43 mL, 2.44 mmol) to afford(R)-3-(3-((5-ethynylpyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde(210 mg, 51%).

Step 2: Preparation of(R,Z)-2-((1-(2-fluoro-5-((3-oxoisofuran-1(3H)-ylidene)methyl)benzol)pyrrolidin-3-yl)amino)pyrimidine-5-carbonitrile

This compound was made using the procedure described for example 11(Step 2). Thus, the intermediate compound (Step 1)(210 mg, 0.63 mol) wasreacted with dimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate(150 mg, 0.63 mmol), triethylamine (0.13 mL, 0.93 mmol) to affordintermediate compound(R,Z)-2-((1-(2-fluoro-5-((3-oxoisofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidin-3-yl)amino)pyrimidine-5-carbonitrile(164 mg, 58%).

Step 3: Preparation of(R)-2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)amino)pyrimidine-5-carbonitrile

This compound was made using the procedure described for example 11(Step 3). Thus, the intermediate compound (Step 2)(164 mg, 0.36 mmol)was reacted with hydrazine monohydrate (164 mg, 0.36 mmol) to affordtitle compound (103 mg, 61%).

¹H-NMR (CDCl₃, 400 MHz): δ 9.93-9.81 (m, 1H), 8.50-8.43 (m, 2H),7.79-7.62 (m, 3H), 7.41-7.27 (m, 3H), 7.07-6.99 (m, 1H), 5.83-5.76 (m,1H), 4.71-4.55 (m, 1H), 4.27 (d, 2H), 4.05-4.00 (m, 0.5H), 3.88-3.62 (m,2H), 3.52-3.44 (m, 1H), 3.29-3.25 (m, 0.5H), 2.42-2.28 (m, 1H),2.09-1.96 (m, 1H).

Example 127(R)-2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)ethyl)benzoyl)pyrrolidin-3-yl)amino)nicotinonitrile; (I-127) Step 1: Preparation of(R)-2-((1-(2-fluoro-5-formylbenzoyl)pyrrolidine-3-yl)amino)nicotinonitrile

This compound was made using the procedure described for example 11(Step 1). Thus, (R)-2-(pyrrolidin-3-ylamino)nicotinonitrile (300 mg,1.59 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (205 mg, 1.22mmol), 0-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU, 785 mg, 2.07 mmol), N,N-diisopropylethylamine (DIPEA, 0.55 mL, 3.18 mmol) to afford(R)-2-((1-(2-fluoro-5-formylbenzoyl)pyrrolidine-3-yl)amino)nicotinonitrile(275 mg, 51%).

Step 2: Preparation of(R,Z)-2-((1-(2-fluoro-5-((3-oxoisofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidine-3-yl)amino)nicotinonitrile

This compound was made using the procedure described for example 11(Step 2). Thus, the intermediate compound (Step 1)(275 mg, 0.81 mmol)was reacted withdimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (196 mg, 0.81mmol), triethylamine (1.7 mL, 1.22 mmol) to afford intermediate compound(R,Z)-2-((1-(2-fluoro-5-((3-oxoisofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidine-3-yl)amino)nicotinonitrile(155 mg, 42%).

Step 3: Preparation of(R)-2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)amino)nicotinonitrile

This compound was made using the procedure described for example 11(Step 3). Thus, the intermediate compound (Step 2)(155 mg, 0.34 mmol)was reacted with hydrazine monohydrate (34 uL, 0.68 mmol) to affordtitle compound (78 mg, 49%).

¹H-NMR (DMSO, 400 MHz): δ 12.59 (d, 1H), 8.28 (m, 2H), 7.85 (m, 4H),7.38 (m, 2H), 7.22 (m, 2H), 6.72 (m, 1H), 4.57 (m, 1H), 4.32 (d, 2H),3.75 (m, 1H), 3.46 (m, 2H), 3.21 (m, 1H), 2.10 (m, 2H).

Example 128(R)-4-(4-fluoro-3-(3-(pyridin-2-ylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-128) Step 1: Preparation of(R)-4-fluoro-3-(3-(pyridin-2-ylamino)pyrrolidine-1-carbonyl)benzaldehyde

This compound was made using the procedure described for example 11(Step 1). Thus, (R)—N-(pyrrolidin-3-yl)pyridine-2-amine (250 mg, 0.92mmol) was reacted with 2-fluoro-5-formylbenzoic acid (154 mg, 0.92mmol), 0-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU, 453 mg, 1.19 mmol), N,N-diisopropylethylamine (DIPEA, 0.32 mL, 1.83 mmol) to afford(R)-4-fluoro-3-(3-(pyridin-2-ylamino)pyrrolidine-1-carbonyl)benzaldehyde(178 m g, 62%).

Step 2: Preparation of(R,Z)-3-(4-fluoro-3-(3-(pyridin-2-ylamino)pyrrolidine-1-carbonyl)benzylidene)isofuran-1(3H)-one

This compound was made using the procedure described for example 11(Step 2). Thus, the intermediate compound (Step 1)(178 mg, 0.57 mmol)was reacted withdimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (138 mg, 0.57mmol), triethylamine (0.12 mL, 0.85 mmol) to afford intermediatecompound(R,Z)-3-(4-fluoro-3-(3-(pyridin-2-ylamino)pyrrolidine-1-carbonyl)benzylidene)isofuran-1(3H)-one (144 mg, 59%).

Step 3: Preparation of(R)-4-(4-fluoro-3-(3-(pyridin-2-ylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 11(Step 3). Thus, the intermediate compound (Step 2)(144 mg, 0.34 mmol)was reacted with hydrazine monohydrate (33 uL, 0.67 mmol) to affordtitle compound (91 mg, 61%).

¹H-NMR (MeOD, 400 MHz): δ 8.35-8.31 (m, 1H), 7.95-7.93 (m, 1H),7.88-7.81 (m, 2H), 7.76-7.73 (m, 1H), 7.45-7.39 (m, 3H), 7.34-7.32 (m,1H), 7.15-7.08 (m, 2H), 4.67-4.30 (m, 1H), 4.38-4.31 (d, 2H), 3.98-3.12(m, 5H), 2.35-2.19 (m, 1H), 2.06-1.88 (m, 1H).

Example 129(R)-2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)amino)-N,N-dimethylnicotinamide; (I-129) Step 1: Preparation of(R)-2-((1-(2-fluoro-5-formylbenzoyl)pyrrolidin-3-yl)amino)-N,N-dimethylnicotinamide

This compound was made using the procedure described for example 11(Step 1). Thus, (R)—N,N-dimethyl-2-(pyrrolidin-3-ylamino)nicotinamide(320 mg, 1.36 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (300mg, 1.36 mmol), 0-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU, 673 mg, 1.77 mmol), N,N-diisopropylethylamine (DIPEA, 0.48 mL, 2.73 mmol) to afford(R)-2-((1-(2-fluoro-5-formylbenzoyl)pyrrolidin-3-yl)amino)-N,N-dimethylnicotinamide(220 mg, 42%).

Step 2: Preparation of(R,Z)-2-((1-(2-fluoro-5-((3-oxoisofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidin-3-yl)amino)-N,N-dimethylnicotinamide

This compound was made using the procedure described for example 11(Step 2). Thus, the intermediate compound (Step 1)(220 mg, 0.57 mmol)was reacted withdimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (139 mg, 0.57mmol), triethylamine (0.2 mL, 0.86 mmol) to afford intermediate compound(R,Z)-2-((1-(2-fluoro-5-((3-oxoisofuran-1(3H)-ylidene)methyl)benzoyl)pyrrolidin-3-yl)amino)-N,N-dimethylnicotinamide(109 mg, 38%).

Step 3: Preparation of(R)-2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)amino)-N,N-dimethylnicotinamide

This compound was made using the procedure described for example 11(Step 3). Thus, the intermediate compound (Step 2)(109 mg, 0.22 mmol)was reacted with hydrazine monohydrate (22 uL, 0.44 mmol) to affordtitle compound (39 mg, 35%).

¹H-NMR (MeOD, 400 MHz): δ 8.36 (m, 1H), 7.88 (m, 4H), 7.44 (m, 3H), 7.13(m, 1H), 6.69 (m, 1H), 4.56 (m, 1H), 4.36 (d, 2H), 3.85 (m, 1H), 3.55(m, 2H), 3.21 (m, 1H), 3.02 (s, 6H), 2.30 (m, 1H), 2.07 (m, 1H).

Example 130(R)-4-(3-(3-((5-bromopyridin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-130) Step 1: Preparation of(R)-3-(3-((5-bromopyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde

This compound was made using the procedure described for example 11(Step 1). Thus, (R)-5-bromo-N-(pyrrolidin-3-yl)pyrimidine-2-amine (320mg, 1.32 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (221 mg,1.32 mmol), 0-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU, 649 mg, 1.71 mmol), N,N-diisopropylethylamine (DIPEA, 0.46 mL, 2.63 mmol) to afford(R)-3-(3-((5-bromopyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzaldehyde(274 mg, 53%).

Step 2: Preparation of(R,Z)-3-(4-fluoro-3-(3-((5-bromopyrimidin-2-yl)aminopyrrolidine-1-carbonyl)benzylidene)isofuran-1(3H)-one

This compound was made using the procedure described for example 11(Step 2). Thus, the intermediate compound (Step 1)(274 mg, 0.70 mmol)was reacted withdimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (169 mg, 0.70mmol), triethylamine (0.15 mL, 1.04 mmol) to afford intermediatecompound(R,Z)-3-(4-fluoro-3-(3-((5-bromopyrimidin-2-yl)aminopyrrolidine-1-carbonyl)benzylidene)isofuran-1(3H)-one(217 mg, 61%).

Step 3: Preparation of(R)-4-(4-fluoro-3-(3-((5-bromopyrimidin-2-yl)aminopyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 11(Step 3). Thus, the intermediate compound (Step 2)(217 mg, 0.43 mmol)was reacted with hydrazine monohydrate (45 uL, 0.86 mmol) to affordtitle compound (131 mg, 59%).

¹H-NMR (CDCl₃, 400 MHz): δ 9.93-9.81 (m, 1H), 8.50-8.43 (m, 2H),7.79-7.62 (m, 3H), 7.41-7.27 (m, 3H), 7.07-6.99 (m, 1H), 5.83-5.76 (m,1H), 4.71-4.55 (m, 1H), 4.27 (d, 2H), 4.05-4.00 (m, 0.5H), 3.88-3.62 (m,2H), 3.52-3.44 (m, 1H), 3.29-3.25 (m, 0.5H), 2.42-2.28 (m, 1H),2.09-1.96 (m, 1H).

Example 131(R)-4-(4-fluoro-3-(3-((5-(trifluoromethyl)pyridin-2-yl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-131) Step 1: Preparation of(R)-4-fluoro-3-(3-((5-(trifluoromethylpyridin-2-yl)aminopyrrolidine-1-carbonyl)benzaldehyde

This compound was made using the procedure described for example 11(Step 1). Thus, (R)—N-(pyrrolidin-3-yl)-5-(trifluoromethyl-2-amine (200mg, 0.86 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (145 mg,0.86 mmol), 0-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU, 426 mg, 1.12 mmol), N,N-diisopropylethylamine (DIPEA, 0.31 mL, 1.72 mmol) to afford(R)-4-fluoro-3-(3-((5-(trifluoromethylpyridin-2-yl)aminopyrrolidine-1-carbonyl)benzaldehyde(174 mg, 53%).

Step 2: Preparation of(R,Z)-3-(4-fluoro-3-(3-((5-(trifluoromethylpyridin-2-yl)amino)pyrrolidine-1-carbonyl)benzylidene)isofuran-1(3H)-one

This compound was made using the procedure described for example 11(Step 2). Thus, the intermediate compound (Step 1)(174 mg, 0.46 mmol)was reacted withdimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (111 mg, 0.46mmol), triethylamine (96 uL, 0.69 mmol) to afford intermediate compoundR,Z)-3-(4-fluoro-3-(3-((5-(trifluoromethylpyridin-2-yl)amino)pyrrolidine-1-carbonyl)benzylidene)isofuran-1(3H)-one(139 mg, 61%).

Step 3: Preparation of(R)-4-(4-fluoro-3-(3-((5-(trifluoromethyl)pyridin-2-yl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 11(Step 3). Thus, the intermediate compound (Step 2)(139 mg, 0.28 mmol)was reacted with hydrazine monohydrate (28 uL, 0.56 mmol) to affordtitle compound (85 mg, 59%).

¹H-NMR (DMSO, 400 MHz): δ 12.59 (d, 1H), 8.29 (m, 2H), 7.85 (m, 3H),7.62 (m, 2H), 7.39 (m, 2H), 7.20 (m, 1H), 6.58 (m, 1H), 4.38 (m, 1H),4.32 (d, 2H), 3.75 (m, 1H), 3.47 (m, 2H), 3.21 (m, 1H), 2.20 (m, 1H),1.92 (m, 1H).

Example 132(R)-4-(4-fluoro-3-(3-((4-(trifluoroethyl)pyridin-2-yl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-132) Step 1: Preparation of(R)-4-fluoro-3-(3-((4-(trifluoromethyl)pyridin-2-yl)amino)pyrrolidine-1-carbonyl)benzaldehyde

This compound was made using the procedure described for example 11(Step 1). Thus,(R)—N-(pyrrolidin-3-yl)-4-(trifluoromethyl)pyridine-2-amine (200 mg,0.86 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (145 mg, 0.86mmol), 0-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU, 426 mg, 1.12 mmol), N,N-diisopropylethylamine (DIPEA, 0.31 mL, 1.72 mmol) to afford(R)-4-fluoro-3-(3-((4-(trifluoromethyl)pyridin-2-yl)amino)pyrrolidine-1-carbonyl)benzaldehyde(174 mg, 53%).

Step 2: Preparation of(R,Z)-3-(4-fluoro-3-(3-((4-(trifluoromethyl)pyridin-2-yl)amino)pyrrolidine-1-carbonyl)benzylidene)isofuran-1(3H)-one

This compound was made using the procedure described for example 11(Step 2). Thus, the intermediate compound (Step 1)(174 mg, 0.46 mmol)was reacted withdimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (111 mg, 0.46mmol), triethylamine (96 uL, 0.69 mmol) to afford intermediate compound(R,Z)-3-(4-fluoro-3-(3-((4-(trifluoromethyl)pyridin-2-yl)amino)pyrrolidine-1-carbonyl)benzylidene)isofuran-1(3H)-one(139 mg, 61%).

Step 3: Preparation of(R)-4-(4-fluoro-3-(3-((4-(trifluoromethyl)pyridin-2-yl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 11(Step 3). Thus, the intermediate compound (Step 2)(139 mg, 0.28 mmol)was reacted with hydrazine monohydrate (28 uL, 0.56 mmol) to affordtitle compound (85 mg, 59%).

¹H-NMR (DMSO, 400 MHz): δ 12.59 (d, 1H), 8.29 (m, 2H), 7.85 (m, 3H),7.62 (m, 2H), 7.39 (m, 2H), 7.20 (m, 1H), 6.58 (m, 1H), 4.38 (m, 1H),4.32 (d, 2H), 3.75 (m, 1H), 3.47 (m, 2H), 3.21 (m, 1H), 2.20 (m, 1H),1.92 (m, 1H).

Example 1334-(3-(3-(benzylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;I-133 Step 1: Preparation of4-(3-(3-(benzylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

Benzyl bromide (0.10 mL, 0.86 mmol) and K₂CO₃ (119 mg, 0.86 mmol) wasadded to a suspension of the example 3 product (150 mg, 0.43 mmol) indimethylformamide (DMF, 8 mL) and stirred for 8 hours at 80° C. Thereaction was cooled to room temperature and concentrated in vacuo, addeddichloromethane and washed a solution of sodium bicarbonate and water.The combined organic layers were dried over MgSO₄, filtered, evaporatedin vacuo and purified using silica chromatography to afford titlecompound (86 mg, 45%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.17 (s, 1H), 8.47-8.46 (m, 1H), 7.82-7.72(m, 3H), 7.54-7.50 (m, 1H), 7.37-7.31 (m, 5H), 7.06-7.01 (m, 1H),4.37-4.32 (m, 1H), 4.29 (s, 2H), 4.19-4.16 (m, 1H), 3.89-3.73 (m, 5H).

Example 134 4-(4-fluoro-3-(3-((3,3,3-trifluoropropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-134) Step 1: Preparation of4-(4-fluoro-3-(3-((3,3,3-trifluoropropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 133(Step 1). Thus,4-(3-(3-aminoazetidin-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(150 mg, 0.43 mmol) was reacted with 3-bromo-1,1,1-trifluoropropan (0.25mL, 0.86 mmol), K₂CO₃ (119 mg, 0.86 mmol) to afford title compound (98mg, 51%).

¹H-NMR (MeOD, 400 MHz): δ 8.38-8.35 (m, 1H), 7.95-7.92 (m, 1H),7.89-7.82 (m, 2H), 7.52-7.50 (m, 1H), 7.45-7.43 (m, 1H), 7.17-7.12 (m,1H), 4.37 (s, 2H), 4.30-4.28 (m, 1H), 4.16-4.14 (m, 1H), 3.86-3.83 (m,1H), 3.78-3.76 (m, 1H), 3.68-3.66 (m, 1H), 2.48-2.42 (m, 2H), 1.92-1.85(m, 2H).

Example 135(R)-4-(3-(3-(azetidin-1-yl)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-135) Step 1: Preparation of(S)-1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidine-3-ylmethansulfonate

The example 5 intermediate compound(S)-4-(4-fluoro-3-(3-hydroxypyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (539 mg, 1.25 mmol) in dichloromethane (7 mL) cooled to 0° C.was added triethylamine (0.1 mL, 1.50 mmol), methanesulfonyl chloride(MsCl, 0.11 mL, 1.38 mmol), and the mixture was stirred at roomtemperature for 3 h. The reaction mixture was concentrated in vacuo,added dichloromethane and washed with aqueous sodium bicarbonate andwater. The combined organic layers were dried over MgSO₄, filtered,evaporated in vacuo to afford(S)-1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidine-3-ylmethanesulfonate(434 mg, 78%).

Step 2: Preparation of(R)-4-(3-(3-(azetidin-1-yl)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

The intermediate compound (Step 1)(434 mg, 0.97 mmol) indimethylformamide (DMF, 5 mL) was added azetidine (0.20 mL, 2.93 mmol),Li₂CO₃ (216 mg, 2.93 mmol) and the mixture was stirred at 80° C. for 16h. The reaction mixture was concentrated in vacuo, added dichloromethaneand washed with aqueous ammonium chloride and water. The combinedorganic layers were dried over MgSO₄, filtered, evaporated in vacuo andpurified using silica chromatography to afford the title compound (117mg, 45%).

¹H-NMR (DMSO, 400 MHz): δ 12.61 (s, 1H), 8.26 (d, 1H), 7.96 (t, 1H),7.91-7.80 (m, 2H), 7.46-7.35 (m, 1H), 7.25-7.18 (m, 1H), 4.33 (s, 2H),3.73-3.58 (m, 1H), 3.44-3.39 (m, 1H), 3.27-3.19 (m, 1H), 3.13-3.08 (m,1H), 2.98 (t, 1H), 2.86 (d, 1H), 2.77-2.61 (m, 1H), 2.16 (t, 2H), 2.03(t, 2H), 1.77-1.62 (m, 2H).

Example 136(R)-4-(3-([1,3′-bipyrrolidine]-1′-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-136) Step 1: Preparation of(S)-1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidine-3-ylmethansulfonate

The intermediate compound(S)-1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidine-3-yl-methansulfonatewas made using the procedure described for example 135 (Step 1) in ayield of 78% (434 mg).

Step 2: Preparation of(R)-4-(3-([1,3′-bipyrrolidine]-1′-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 135(Step 2). Thus, the intermediate compound (Step 1)(434 mg, 0.97 mmol)was reacted with pyrrolidine (0.22 mL, 2.93 mmol), Li₂CO₃ (216 mg, 2.93mmol) to afford title compound (130 mg, 32%).

¹H-NMR (MeOD, 400 MHz): δ 8.35 (d, 1H), 7.93 (d, 1H), 7.90-7.79 (m, 2H),7.54-7.44 (m, 1H), 7.42-7.37 (m, 1H), 7.18-7.11 (m, 1H), 4.37 (s, 2H),3.85-3.74 (m, 1H), 2.65 (t, 2H), 2.57-2.50 (m, 1H), 2.40 (t, 1H),2.23-2.07 (m, 1H), 1.97-1.90 (m, 1H), 1.85 (m, 2H), 1.76 (m, 2H).

Example 137(R)-4-(4-fluoro-3-(3-(piperidin-1-yl)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-137) Step 1: Preparation of(S)-1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidine-3-ylmethansulfonate

The intermediate compound(S)-1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidine-3-yl-methansulfonatewas made using the procedure described for example 135 (Step 1) in ayield of 78% (434 mg).

Step 2: Preparation of(R)-4-(4-fluoro-3-(3-(piperidin-1-yl)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 135(Step 2). Thus, the intermediate compound (Step 1)(434 mg, 0.97 mmol)was reacted with piperidine (0.10 mL, 2.93 mmol), Li₂CO₃ (216 mg, 2.93mmol) to afford title compound (88 mg, 21%).

¹H-NMR (DMSO, 400 MHz): δ 12.61 (s, 1H), 8.26 (d, 1H), 7.97 (d, 1H),7.91-7.80 (m, 2H), 7.46-7.39 (m, 1H), 7.38-7.35 (m, 1H), 7.25-7.19 (m,1H), 4.32 (s, 2H), 3.75-3.59 (m, 1H), 3.39-3.36 (m, 0.5H), 3.29-3.12 (m,2H), 2.97 (t, 0.5H), 2.83-2.71 (m, 1H), 2.42-2.28 (m, 3H), 2.15-1.98 (m,2H), 1.73-1.63 (m, 1H), 1.51-1.29 (m, 6H).

Example 138 (R)-4-(4-fluoro-3-(3-(p-tolylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one; (I-138) Step1: Preparation of(R)-4-fluoro-3-(3-(p-tolylamino)pyrrolidine-1-carbonyl)benzaldehyde

This compound was made using the procedure described for example 11(Step 1). Thus,(R)-4-fluoro-3-(3-(p-tolylamino)pyrrolidine-1-carbonyl)benzaldehyde (200mg, 1.13 mmol) was reacted with 2-fluoro-5-formylbenzoic acid (190 mg,1.13 mmol), 0-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU, 559 mg, 1.48 mmol), N,N-diisopropylethylamine (DIPEA, 0.40 mL, 2.27 mmol) to afford(R)-4-fluoro-3-(3-(p-tolylamino)pyrrolidine-1-carbonyl)benzaldehyde (230mg, 62%).

Step 2: Preparation of(R,Z)-3-(4-fluoro-3-(3-(p-tolylamino)pyrrolidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one

This compound was made using the procedure described for example 11(Step 2). Thus, the intermediate compound (Step 1)(230 mg, 0.70 mmol)was reacted withdimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (170 mg, 0.70mmol), triethylamine (0.15 mL, 1.10 mmol) to afford intermediatecompound(R,Z)-3-(4-fluoro-3-(3-(p-tolylamino)pyrrolidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one(190 mg, 61%).

Step 3: Preparation of(R)-4-(4-fluoro-3-(3-(p-tolylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 11(Step 3). Thus, the intermediate compound (Step 2)(190 mg, 0.43 mmol)was reacted with hydrazine monohydrate (42 uL, 0.86 mmol) to affordtitle compound (129 mg, 66%).

¹H-NMR (DMSO, 400 MHz): δ 12.59 (d, 1H), 8.26 (m, 1H), 7.85 (m, 3H),7.60 (m, 1H), 7.36 (m, 1H), 7.20 (m, 1H), 6.88 (dd, 2H), 6.48 (dd, 2H),5.60 (m, 1H), 4.32 (d, 2H), 3.91 (m, 2H), 3.52 (m, 2H), 3.11 (m, 1H),2.14 (m, 1H), 2.12 (s, 3H), 1.90 (m, 1H).

Example 139(R)-4-(4-fluoro-3-(3-(phenylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-139) Step 1: Preparation of(R)-4-fluoro-3-(3-(phenylamino)pyrrolidine-1-carbonyl)benzaldehyde

This compound was made using the procedure described for example 11(Step 1). Thus, (R) N-phenylpyrrolidine-3-amine (200 mg, 1.23 mmol) wasreacted with 2-fluoro-5-formylbenzoic acid (207 mg, 1.23 mmol),0-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU, 607 mg, 1.60 mmol), N,N-diisopropyl ethylamine (DIPEA, 0.43 mL,2.46 mmol) to afford(R)-4-fluoro-3-(3-(phenylamino)pyrrolidine-1-carbonyl)benzaldehyde (238mg, 62%).

Step 2: Preparation of(R,Z)-3-(4-fluoro-3-(3-(phenylamino)pyrrolidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one

This compound was made using the procedure described for example 11(Step 2). Thus, the intermediate compound (Step 1)(238 mg, 0.76 mmol)was reacted withdimethyl(3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (185 mg, 0.76mmol), triethylamine (0.16 mL, 1.14 mmol) to afford intermediatecompound(R,Z)-3-(4-fluoro-3-(3-(phenylamino)pyrrolidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one(200 mg, 61%).

Step 3: Preparation of(R)-4-(4-fluoro-3-(3-(phenylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 11(Step 3). Thus, the intermediate compound (Step 2)(200 mg, 0.47 mmol)was reacted with hydrazine monohydrate (46 uL, 0.94 mmol) to affordtitle compound (136 mg, 66%).

¹H-NMR (MeOD, 400 MHz): δ 8.39-8.34 (m, 1H), 7.97-7.70 (m, 3H),7.50-7.33 (m, 2H), 7.19-7.07 (m, 3H), 6.70-6.57 (m, 3H), 4.40 (s, 1H),4.33 (s, 1H), 4.17-4.05 (m, 1H), 3.95-3.79 (m, 1H), 3.72-3.47 (m, 2H),3.41-3.16 (m, 1H), 2.37-2.20 (m, 1H), 2.09-1.91 (m, 1H).

Example 1404-(4-fluoro-3-(3-(pyrrolidin-1-ylmethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-140) Step 1: Preparation of(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidine-3-yl)methylmethansulfonate

The intermediate compound (example 7)4-(4-fluoro-3-(3-(hydroxymethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one(460 mg, 1.25 mmol) in dichloromethane (7 mL) cooled to 0° C. was addedtriethylamine (0.1 mL, 1.50 mmol), methanesulfonyl chloride (MsCl, 0.11mL, 1.38 mmol), and the mixture was stirred at room temperature for 3 h.The reaction mixture was concentrated in vacuo, added dichloromethaneand washed with aqueous sodium bicarbonate and water. The combinedorganic layers were dried over MgSO₄, filtered, evaporated in vacuo toafford(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidine-3-yl)methylmethansulfonate(417 mg, 75%).

Step 2: Preparation of4-(4-fluoro-3-(3-(pyrrolidin-1-ylmethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

The intermediate compound (Step 1)(417 mg, 0.94 mmol) in 1,4-dioxane (5mL) was added pyrrolidine (0.27 mL, 4.00 mmol) and the mixture wasstirred at 80° C. for 16 h. The reaction mixture was concentrated invacuo, added dichloromethane and washed with aqueous ammonium chlorideand water. The combined organic layers were dried over MgSO₄, filtered,evaporated in vacuo and purified using silica chromatography to affordthe title compound (138 mg, 35%).

¹H-NMR (CDCl₃, 400 MHz): δ 9.85 (s, 1H), 8.46-8.44 (m, 1H), 7.78-7.70(m, 3H), 7.49-7.47 (m, 1H), 7.32-7.27 (m, 1H), 7.03-6.98 (m, 1H),4.29-4.24 (m, 3H), 4.14-4.10 (t, 1H), 3.85-3.77 (m, 2H), 2.91-2.64 (m,3H), 2.48 (s, 4H), 1.77 (s, 4H).

Example 1414-(4-fluoro-3-(3-(piperidin-1-ylethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-141) Step 1: Preparation of(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidine-3-yl)methylmethanesulfonate

The intermediate compound(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidine-3-yl)methylmethansulfonatewas made using the procedure described for example 140 (Step 1) in ayield of 75% (417 mg).

Step 2: Preparation of4-(4-fluoro-3-(3-(piperidin-1-ylmethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 140(Step 2). Thus, the intermediate compound (Step 1)(417 mg, 0.94 mmol)was reacted with piperidine (0.44 mL, 4.00 mmol) to afford titlecompound (138 mg, 35%).

¹H-NMR (CDCl₃, 400 MHz): δ 9.94 (s, 1H), 8.46 (m, 1H), 7.78-7.70 (m,3H), 7.50-7.48 (m, 1H), 7.31-7.27 (m, 1H), 7.01 (t, 1H), 4.27-4.23 (t,1H), 4.26 (s, 2H), 7.13-4.09 (t, 1H), 3.83-3.70 (m, 2H), 2.88-2.84 (m,1H), 2.57-2.55 (m, 2H), 2.32 (s, 4H), 1.54 (s, 4H), 1.42 (s, 2H).

Example 1424-(3-(3-(azetidin-1-ylmethyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-142) Step 1: Preparation of(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidine-3-yl)methylmethansulfonate

The intermediate compound(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidine-3-yl)methyl methansulfonate was made using the procedure described forexample 140 (Step 1) in a yield of 75% (417 mg).

Step 2: Preparation of4-(3-(3-(azetidin-1-ylmethyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 140(Step 2). Thus, the intermediate compound (Step 1)(417 mg, 0.94 mmol)was reacted with azetidine (0.28 mL, 4.00 mmol) to afford title compound(154 mg, 41%).

¹H-NMR (MeOD, 400 MHz): δ 8.36 (d, 1H), 7.94 (d, 1H), 7.84 (m, 2H), 7.50(m, 2H), 7.13 (t, 1H), 4.38 (s, 2H), 4.19 (t, 1H), 4.09 (m, 1H), 3.74(m, 2H), 3.30 (m, 4H), 2.69 (m, 3H), 2.14 (t, 2H).

Example 1434-(3-(3-((cyclopropylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-143) Step 1: Preparation of(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazine-1-yl)methyl)benzoyl)azetidine-3-yl)methyl methansulfonate

The intermediate compound(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidine-3-yl)methylmethansulfonate was made using the procedure described for example 140(Step 1) in a yield of 75% (417 mg).

Step 2: Preparation of4-(3-(3-((cyclopropylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 140(Step 2). Thus, the intermediate compound (Step 1)(417 mg, 0.94 mmol)was reacted with cyclopropylamine (0.28 mL, 4.00 mmol) to afford titlecompound (206 mg, 54%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.03 (s, 1H), 8.47-8.45 (m, 1H), 7.80-7.71(m, 3H), 7.52-7.48 (m, 1H), 7.32-7.28 (m, 1H), 7.01 (t, 1H), 4.27 (s,2H), 4.26-4.22 (m, 1H), 4.10 (t, 1H), 3.85-3.81 (m, 1H), 3.73-3.70 (m,1H), 2.99-2.88 (m, 2H), 2.81-2.72 (m, 1H), 2.07 (m, 1H), 1.57 (br, 1H),0.45-0.41 (m, 2H), 0.29-0.26 (m, 2H).

Example 1444-(4-fluoro-3-(3-((isopropylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-144) Step 1: Preparation of(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazine-1-yl)methyl)benzoyl)azetidine-3-yl)methyl methansulfonate

The intermediate compound(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidine-3-yl)methyl methansulfonate was made using the procedure described forexample 140 (Step 1) in a yield of 75% (417 mg).

Step 2: Preparation of4-(4-fluoro-3-(3-((isopropylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 140(Step 2). Thus, the intermediate compound (Step 1)(417 mg, 0.94 mmol)was reacted with isopropylamine (0.34 mL, 4.00 mmol) to afford titlecompound (234 mg, 61%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.20 (br, 1H), 8.47-8.45 (m, 1H), 7.80-7.70(m, 3H), 7.51-7.49 (dd, 1H), 7.32-7.28 (m, 1H), 7.01 (t, 1H), 4.27 (s,2H), 4.28-4.23 (m, 1H), 4.12 (t, 1H), 3.84-3.81 (dd, 1H), 3.75-3.71 (dd,1H), 2.88-2.69 (m, 4H), 1.05-1.03 (dd, 6H).

Example 1454-(3-(3-(((cyclopropylmethyl)amino)ethyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-145) Step 1: Preparation of(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazine-1-yl)methyl)benzoyl)azetidine-3-yl)methylmethansulfonate

The intermediate compound(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidine-3-yl)methylmethansulfonate was made using the procedure described for example 140(Step 1) in a yield of 75% (417 mg).

Step 2: Preparation of4-(3-(3-(((cyclopropylmethyl)amino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 140(Step 2). Thus, the intermediate compound (Step 1)(417 mg, 0.94 mmol)was reacted with cyclopropylmethylamine (0.34 mL, 4.00 mmol) to affordtitle compound (189 mg, 48%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.36 (br, 1H), 8.47-8.45 (m, 1H), 7.80-7.71(m, 3H), 7.51-7.49 (m, 1H), 7.32-7.28 (m, 1H), 7.01 (t, 1H), 4.27-4.24(m, 3H), 4.13 (t, 1H), 3.86-3.75 (m, 2H), 2.94-2.75 (m, 3H), 2.48-2.46(dd, 2H), 1.61 (br, 1H), 0.95-0.91 (m, 1H), 0.51-0.46 (m, 2H), 0.12-0.09(m, 2H).

Example 1464-(4-fluoro-3-(3-((isobutylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-146) Step 1: Preparation of(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazine-1-yl)methyl)benzoyl)azetidine-3-yl)methylmethansulfonate

The intermediate compound(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidine-3-yl)methylmethansulfonate was made using the procedure described for example 140(Step 1) in a yield of 75% (417 mg).

Step 2: Preparation of4-(4-fluoro-3-(3-((isobutylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 140(Step 2). Thus, the intermediate compound (Step 1)(417 mg, 0.94 mmol)was reacted with 2-methylpropan-1-amine (0.40 mL, 4.00 mmol) to affordtitle compound (207 mg, 52%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.69 (br, 1H), 8.47-8.45 (m, 1H), 7.80-7.71(m, 3H), 7.50-7.48 (m, 1H), 7.32-7.28 (m, 1H), 7.00 (t, 1H), 4.27-4.23(m, 3H), 4.14 (t, 1H), 3.86-3.78 (m, 2H), 2.93-2.78 (m, 3H), 2.45 (s,1H), 2.44 (s, 1H), 1.81-1.71 (m, 1H), 0.91 (s, 3H), 0.89 (s, 3H).

Example 1474-(3-(3-((tert-butylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-147) Step 1: Preparation of(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazine-1-yl)methyl)benzoyl)azetidine-3-yl)methylmethansulfonate

The intermediate compound(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidine-3-yl)methylmethansulfonate was made using the procedure described for example 140(Step 1) in a yield of 75% (417 mg).

Step 2: Preparation of4-(3-(3-((tert-butylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 140(Step 2). Thus, the intermediate compound (Step 1)(417 mg, 0.94 mmol)was reacted with 2-methylpropan-2-amine (0.42 mL, 4.00 mmol) to affordtitle compound (71 mg, 18%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.49 (br, 1H), 8.47-8.45 (m, 1H), 7.80-7.72(m, 3H), 7.52-7.48 (m, 1H), 7.31-7.28 (m, 1H), 7.01 (t, 1H), 4.27-4.22(m, 3H), 4.14 (t, 1H), 2.90-2.75 (m, 3H), 1.14 (s, 9H).

Example 1484-(3-(3-((cyclobutylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-148) Step 1: Preparation of(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazine-1-yl)methyl)benzoyl)azetidine-3-yl)methylmethansulfonate

The intermediate compound(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidine-3-yl)methylmethansulfonate was made using the procedure described for example 140(Step 1) in a yield of 75% (417 mg).

Step 2: Preparation of4-(3-(3-((cyclobutylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 140(Step 2). Thus, the intermediate compound (Step 1)(417 mg, 0.94 mmol)was reacted with cyclobutylamine (0.43 mL, 4.00 mmol) to afford titlecompound (138 mg, 35%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.33 (br, 1H), 8.47-8.45 (m, 1H), 7.80-7.71(m, 3H), 7.50-7.48 (m, 1H), 7.31-7.28 (m, 1H), 7.00 (t, 1H), 4.27-4.22(m, 3H), 4.11 (t, 1H), 3.83-3.72 (m, 2H), 3.23 (m, 1H), 2.83-2.72 (m,3H), 2.23-2.17 (m, 2H), 1.71-1.62 (m, 5H).

Example 1494-(4-fluoro-3-(3-((prop-2-yn-1-ylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-149) Step 1: Preparation of(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazine-1-yl)methyl)benzoyl)azetidine-3-yl)methyl methansulfonate

The intermediate compound(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidine-3-yl)methylmethansulfonate was made using the procedure described for example 140(Step 1) in a yield of 75% (417 mg).

Step 2: Preparation of4-(4-fluoro-3-(3-((prop-2-yn-1-ylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 140(Step 2). Thus, the intermediate compound (Step 1)(417 mg, 0.94 mmol)was reacted with propargylamine (0.27 mL, 4.00 mmol) to afford titlecompound (163 mg, 43%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.61 (s, 1H), 8.48-8.46 (m, 1H), 7.80-7.71(m, 3H), 7.51-7.49 (m, 1H), 7.32-7.28 (m, 1H), 7.01 (t, 1H), 4.28-4.24(m, 3H), 4.12 (t, 1H), 3.88-3.76 (m, 2H), 3.43 (m, 2H), 3.00-2.87 (m,2H), 2.78-2.72 (m, 1H), 2.27-2.23 (m, 1H), 1.45 (br, 1H).

Example 1504-(4-fluoro-3-(3-((phenylamino)ethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(I-150) Step 1: Preparation of(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazine-1-yl)methyl)benzoyl)azetidine-3-yl)methylmethansulfonate

The intermediate compound(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidine-3-yl)methylmethansulfonate was made using the procedure described for example 140(Step 1) in a yield of 75% (417 mg).

Step 2: Preparation of4-(4-fluoro-3-(3-((phenylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 140(Step 2). Thus, the intermediate compound (Step 1)(417 mg, 0.94 mmol)was reacted with aniline (0.36 mL, 4.00 mmol) to afford title compound(45 mg, 11%).

¹H-NMR (CDCl₃, 400 MHz): δ 11.25 (s, 1H), 8.48-8.46 (m, 1H), 7.77-7.70(m, 3H), 7.51-7.49 (dd, 1H), 7.33-7.29 (m, 1H), 7.17 (t, 2H), 7.00 (t,1H), 6.72 (t, 1H), 6.59 (m, 2H), 4.31-4.27 (m, 3H), 4.17-4.09 (m, 1H),3.39-3.78 (m, 2H), 3.41-3.31 (m, 2H), 2.95-2.89 (m, 1H).

Example 1511-((((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)methyl)amino)methyl)cyclopropanecarbonitrile; (I-151) Step 1:Preparation of(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazine-1-yl)methyl)benzoyl)azetidine-3-yl)methylmethansulfonate

The intermediate compound(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidine-3-yl)methylmethansulfonate was made using the procedure described for example 140(Step 1) in a yield of 75% (417 mg).

Step 2: Preparation of1-((((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)methyl)amino)methyl)cyclopropanecarbonitrile

This compound was made using the procedure described for example 140(Step 2). Thus, the intermediate compound (Step 1)(417 mg, 0.94 mmol)was reacted with 1-(aminomethyl)cyclopropanecarbonitrile (384 mg, 4.00mmol) to afford title compound (121 mg, 29%).

¹H-NMR (MeOD, 400 MHz): δ 8.36 (d, 1H), 7.82-7.95 (m, 3H), 7.44-7.46 (m,2H), 7.13 (t, 1H), 4.37 (s, 2H), 4.21 (t, 1H), 4.10 (t, 1H), 3.74-3.85(m, 2H), 2.80-2.87 (m, 3H), 2.68-2.70 (m, 2H), 1.20 (s, 2H), 0.95 (s,2H).

Example 1521-(((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)methyl)amino)cyclopropanecarbonitrile; (I-152) Step 1: Preparation of(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazine-1-yl)methyl)benzoyl)azetidine-3-yl)methylmethansulfonate

The intermediate compound(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidine-3-yl)methylmethansulfonate was made using the procedure described for example 140(Step 1) in a yield of 75% (417 mg).

Step 2: Preparation of1-(((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)methyl)amino)cyclopropanecarbonitrile

This compound was made using the procedure described for example 140(Step 2). Thus, the intermediate compound (Step 1)(417 mg, 0.94 mmol)was reacted with 1-aminocyclopropanecarbonitrile (474 mg, 4.00 mmol) toafford title compound (44 mg, 11%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.39 (s, 1H), 8.48-8.46 (m, 1H), 7.77-7.72(m, 3H), 7.53-7.49 (m, 1H), 7.35-7.29 (m, 1H), 7.02 (t, 1H), 4.28 (s,2H), 4.27-4.09 (m, 2H), 3.86-3.69 (m, 2H), 2.75 (m, 1H), 1.90 (m, 1H),1.64 (s, 2H), 1.23 (m, 2H), 1.00 (m, 2H).

Example 1534-(3-(3-((cyclopropyl(prop-2-yn-1-yl)amino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-153) Step 1: Preparation of4-(3-(3-((cyclopropyl(prop-2-yn-1-yl)amino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

4-(3-(3-((cyclopropylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(example 144) (126 mg, 0.52 mmol) in dimethylformamide (DMF, 3 mL) wasadded Na₂CO₃ (63 mg, 1.56 mmol), 3-bromoprop-1-yn (0.16 mL, 2.60 mmol)and the mixture was stirred at room temperature for 3 h. The reactionmixture was concentrated in vacuo, added dichloromethane and washed withaqueous ammonium chloride and water. The combined organic layers weredried over MgSO₄, filtered, evaporated in vacuo and purified usingsilica chromatography to afford the title compound (190 mg, 82%).

¹H-NMR (CDCl₃, 400 MHz): δ 11.08 (s, 1H), 8.49-8.47 (m, 1H), 7.79-7.71(m, 3H), 7.51-7.49 (m, 1H), 7.32-7.29 (m, 1H), 7.01 (t, 1H), 4.29 (s,2H), 4.26-4.05 (m, 2H), 3.83-3.68 (m, 2H), 3.40 (m, 2H), 2.96-2.87 (m,3H), 2.23 (m, 1H), 1.98-1.95 (m, 1H), 0.53-0.48 (m, 2H), 0.34-0.31 (m,2H).

Example 1544-(3-(3-((cyclopropyl(methyl)amino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-154) Step 1: Preparation of4-(3-(3-((cyclopropyl(methyl)amino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 153(Step 1). Thus, the intermediate compound (example 144)4-(3-(3-((cyclopropylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)-phthalazin-1(2H)-one(150 mg, 0.34 mmol) was reacted with Na₂CO₃ (78 mg, 0.74 mmol) andmethyl iodide (46 uL, 0.74 mmol) to afford the title compound (121 mg,85%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.91 (s, 1H), 8.49-8.47 (m, 1H), 7.79-7.71(m, 3H), 7.51-7.49 (m, 1H), 7.32-7.28 (m, 1H), 7.00 (t, 1H), 4.28 (s,2H), 4.26-4.04 (m, 2H), 3.81-3.66 (m, 2H), 2.96-2.87 (m, 1H), 2.81-2.74(m, 3H), 1.03 (m, 1H), 0.49-0.41 (m, 2H), 0.34-0.26 (m, 2H).

Example 1554-(3-(3-((cyclopropyl(ethyl)amino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(I-155) Step 1: Preparation of4-(3-(3-((cyclopropyl(ethyl)amino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

This compound was made using the procedure described for example 153(Step 1). Thus, the intermediate compound (example 144)4-(3-(3-((cyclopropylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)-phthalazin-1(2H)-one(150 mg, 0.34 mmol) was reacted with Na₂CO₃ (78 mg, 0.74 mmol) and ethyliodide (49 uL, 0.74 mmol) to afford the title compound (113 mg, 77%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.60 (s, 1H), 8.48-8.46 (m, 1H), 7.79-7.71(m, 3H), 7.51-7.49 (m, 1H), 7.32-7.28 (m, 1H), 7.01 (t, 1H), 4.28 (s,2H), 4.26-4.04 (m, 2H), 3.81-3.66 (m, 2H), 2.96-2.87 (m, 1H), 2.81-2.74(m, 2H), 2.65-2.60 (m, 2H), 1.64 (m, 1H), 1.03 (m, 1H), 0.49-0.41 (m,2H), 0.34-0.26 (m, 2H).

Example 1564-(3-(3-(cyclobutylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-onehydrochloride; (I-156) Step 1: Preparation of4-(3-(3-(cyclobutylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-onehydrochloride

The intermediate compound (example 25)4-(3-(3-(cyclobutylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(100 mg, 0.25 mmol) in dichloromethane (3 mL) cooled to 0° C. was added1N solution of hydrochloric acid (0.50 mL, 0.50 mmol). After stirring atroom temperature for 1 h, the solvents were evaporated to afford titlecompound (102 mg, 93%).

¹H-NMR (DMSO, 400 MHz): δ 12.61 (s, 1H), 9.23 (d, 2H), 8.26 (d, 1H),7.97 (d, 1H), 7.89 (t, 1H), 7.83 (t, 1H), 7.50-7.21 (m, 2H), 7.21 (t,1H), 4.33 (s, 2H), 4.10 (t, 1H), 3.97 (t, 1H), 3.67-3.51 (m, 3H), 3.08(m, 1H), 2.76 (m, 1H), 1.99 (t, 2H), 1.69-1.46 (m, 4H).

Example 1574-(3-(3-(cyclopropylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-onehydrochloride; (I-157) Step 1: Preparation of4-(3-(3-(cyclopropylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-onehydrochloride

This compound was made using the procedure described for example 156(Step 1). Thus, the intermediate compound (example 26)4-(3-(3-(cyclopropylcyclopropylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(100 mg, 0.25 mmol) was reacted with 1N solution of hydrochloric acid(0.50 mL, 0.50 mmol) to afford the title compound (97 mg, 91%).

¹H-NMR (MeOD, 400 MHz): δ 8.36 (d, 1H), 7.93 (d, 1H), 7.79-7.89 (m, 2H),7.48-7.54 (m, 1H), 7.42 (d, 1H), 7.15 (t, 1H), 4.00-4.05 (m, 2H),3.75-3.80 (m, 2H), 3.34-3.39 (m, 1H), 3.12 (s, 2H), 1.32-1.36 (m, 1H),0.64-0.72 (m, 2H), 0.41-0.46 (m, 2H).

Example 1584-(3-(3-(cyclopentylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-onehydrochloride; (I-158) Step 1: Preparation of4-(3-(3-(cyclopentylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-onehydrochloride

This compound was made using the procedure described for example 156(Step 1). Thus, the intermediate compound (example 27)4-(3-(3-(cyclopentylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(117 mg, 0.24 mmol) was reacted with 1N solution of hydrochloric acid(0.48 mL, 0.48 mmol) to afford the title compound (99 mg, 90%).

¹H-NMR (DMSO, 400 MHz): δ 12.60 (s, 1H), 9.23 (d, 2H), 8.26 (d, 1H),7.97 (d, 1H), 7.89 (t, 1H), 7.83 (t, 1H), 7.44-7.50 (m, 1H), 7.40 (d,1H), 7.21 (t, 1H), 4.33 (s, 2H), 4.13 (t, 1H), 4.00 (t, 1H), 3.54-3.70(m, 3H), 2.82-2.91 (m, 1H), 1.52-1.67 (m, 4H), 1.43 (brs, 2H), 1.10-1.27(m, 2H).

Example 1594-(4-fluoro-3-(3-(isopropylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-onehydrochloride; (I-159) Step 1: Preparation of4-(4-fluoro-3-(3-(isopropylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-onehydrochloride

This compound was made using the procedure described for example 156(Step 1). Thus, the intermediate compound (example 32)4-(4-fluoro-3-(3-(isopropylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one(100 mg, 0.25 mmol) was reacted with 1N solution of hydrochloric acid(0.50 mL, 0.50 mmol) to afford the title compound (102 mg, 95%).

¹H-NMR (DMSO, 400 MHz): δ 12.61 (s, 1H), 9.23 (d, 2H), 8.27-8.25 (m,1H), 7.97 (d, 1H), 7.91-7.81 (m, 2H), 7.48-7.44 (m, 1H), 7.41-7.39 (m,1H), 7.21 (t, 1H), 4.33 (s, 2H), 4.15-4.10 (m, 2H), 3.66-3.59 (m, 3H),3.17 (d, 1H), 2.68-2.61 (m, 1H), 0.92-0.83 (m, 6H).

Example 1604-(3-(3-((cyclopropylethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-onehydrochloride; (I-160) Step 1: Preparation of4-(3-(3-((cyclopropylmethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-onehydrochloride

This compound was made using the procedure described for example 156(Step 1). Thus, the intermediate compound (example 33)4-(3-(3-((cyclopropylmethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(100 mg, 0.25 mmol) was reacted with 1N solution of hydrochloric acid(0.50 mL, 0.50 mmol) to afford the title compound (98 mg, 89%).

¹H-NMR (DMSO, 400 MHz): δ 12.61 (s, 1H), 9.23 (d, 2H), 8.28-7.97 (m,2H), 7.91-7.81 (m, 2H), 7.48-7.40 (m, 2H), 7.22 (m, 1H), 4.33 (s, 2H),4.13-3.98 (m, 2H), 3.70-3.56 (m, 3H), 2.29 (m, 2H), 0.83-0.72 (m, 1H),0.37-0.32 (m, 2H), 0.06 (m, 2H).

Example 1614-(4-fluoro-3-(3-(isobutylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-onehydrochloride; (I-161) Step 1: Preparation of4-(4-fluoro-3-(3-(isobutylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-onehydrochloride

This compound was made using the procedure described for example 156(Step 1). Thus, the intermediate compound (example 35)4-(4-fluoro-3-(3-(isobutylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one(100 mg, 0.24 mmol) was reacted with 1N solution of hydrochloric acid(0.48 mL, 0.48 mmol) to afford the title compound (101 mg, 95%).

¹H-NMR (MeOD, 400 MHz): δ 8.38-8.35 (m, 1H), 7.95-7.93 (m, 1H),7.89-7.82 (m, 2H), 7.51-7.49 (m, 1H), 7.45-7.43 (m, 1H), 7.15 (t, 1H),4.38 (s, 2H), 4.28-4.26 (m, 1H), 4.16-4.12 (m, 1H), 3.88-3.84 (m, 1H),3.79-3.75 (m, 1H), 3.66-3.64 (m, 1H), 2.31-2.28 (m, 2H), 1.71-1.68 (m,1H), 0.91 (dd, 6H).

Example 1624-(4-fluoro-3-(3-((1-hydroxypropan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2)-onehydrochloride; (I-162) Step 1: Preparation of4-(4-fluoro-3-(3-((1-hydroxypropan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-onehydrochloride

This compound was made using the procedure described for example 156(Step 1). Thus, the intermediate compound (example 36)4-(4-fluoro-3-(3-((1-hydroxypropan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one(100 mg, 0.24 mmol) was reacted with 1N solution of hydrochloric acid(0.48 mL, 0.48 mmol) to afford the title compound (91 mg, 85%).

¹H-NMR (MeOD, 400 MHz): δ 8.36-8.34 (m, 1H), 7.94-7.92 (m, 1H),7.88-7.81 (m, 2H), 7.50-7.49 (m, 1H), 7.46-7.44 (m, 1H), 7.16-7.11 (m,1H), 4.36 (s, 2H), 4.35-4.33 (m, 1H), 4.20-4.17 (m, 1H), 3.90-3.3.83 (m,3H), 3.46-3.43 (m, 1H), 3.39-3.36 (m, 1H), 2.77-2.75 (m, 1H), 1.95 (s,1H), 1.02 (q, 3H).

Example 1634-(3-(3-(butylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-onehydrochloride; (I-163) Step 1: Preparation of4-(3-(3-(butylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-onehydrochloride

This compound was made using the procedure described for example 156(Step 1). Thus, the intermediate compound (example 53)4-(3-(3-(butylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one(100 mg, 0.24 mmol) was reacted with 1N solution of hydrochloric acid(0.48 mL, 0.48 mmol) to afford the title compound (104 mg, 98%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.28 (s, 1H), 9.19 (d, 2H), 8.40-8.38 (m,1H), 7.72-7.66 (m, 1H), 7.44-7.41 (m, 1H), 7.24-7.22 (m, 1H), 6.97-6.92(m, 1H), 4.30-4.27 (m, 1H), 4.20 (s, 2H), 4.11-4.09 (m, 1H), 3.81-3.79(m, 1H), 3.72-3.70 (m, 1H), 3.64-3.62 (m, 1H), 2.50-2.46 (m, 2H), 2.02(s, 1H), 1.40-1.37 (m, 2H), 1.30-1.24 (m, 2H), 0.86-0.80 (m, 5H).

Example 1644-(3-([1,3′-biazetidine]-1′-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-onehydrochloride; (I-164) Step 1: Preparation of4-(3-([1,3′-biazetidine]-1′-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-onehydrochloride

This compound was made using the procedure described for example 156(Step 1). Thus, the intermediate compound (example 75)4-(3-([1,3′-biazetidine]-1′-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(100 mg, 0.25 mmol) was reacted with 1N solution of hydrochloric acid(0.50 mL, 0.50 mmol) to afford the title compound (88 mg, 82%).

¹H-NMR (DMSO, 400 MHz): δ 12.61 (s, 1H), 9.23 (d, 2H), 8.26 (d, 1H),7.78 (d, 1H), 7.89 (t, 1H), 7.83 (t, 1H), 7.45 (m, 2H), 7.22 (t, 1H),4.33 (d, 2H), 4.11 (m, 1H), 3.97 (t, 1H), 3.87 (t, 1H), 3.68 (m, 1H),3.60 (t, 1H), 3.10 (m, 4H), 1.95 (t, 2H).

Example 165(R)-4-(4-fluoro-3-(3-((1-methoxypropan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-onehydrochloride; (I-165) Step 1: Preparation of(R)-4-(4-fluoro-3-(3-((1-methoxypropan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-onehydrochloride

This compound was made using the procedure described for example 156(Step 1). Thus, the intermediate compound (example 83)(R)-4-(4-fluoro-3-(3-((1-methoxypropan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one(117 mg, 0.23 mmol) was reacted with 1N solution of hydrochloric acid(0.46 mL, 0.46 mmol) to afford the title compound (93 mg, 88%).

¹H-NMR (MeOD, 400 MHz): δ 8.38-8.35 (m, 1H), 7.95-7.93 (m, 1H),7.89-7.82 (m, 2H), 7.52-7.50 (m, 1H), 7.45-7.43 (m, 1H), 7.14 (t, 1H),4.38 (s, 2H), 4.12-4.10 (m, 1H), 4.18-4.15 (m, 1H), 3.84-3.77 (m, 3H),3.22-3.19 (m, 1H), 2.89-2.87 (m, 1H), 2.03 (s, 3H), 1.00 (t, 3H).

Example 1661-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)cyclobutanecarbonitrile hydrochloride; (I-166) Step 1: Preparationof1-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)cyclobutanecarbonitrilehydrochloride

This compound was made using the procedure described for example 156(Step 1). Thus, the intermediate compound (example 99)1-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)cyclobutanecarbonitrile(100 mg, 0.23 mmol) was reacted with 1N solution of hydrochloric acid(0.46 mL, 0.46 mmol) to afford the title compound (86 mg, 79%).

¹H-NMR (MeOD, 400 MHz): δ 8.35 (m, 1H), 7.92-7.78 (m, 3H), 7.50-7.43 (m,2H), 7.13 (t, 1H), 4.41-4.39 (m, 1H), 4.36 (s, 2H), 4.23 (m, 1H),3.98-3.92 (m, 2H), 3.85-3.78 (m, 1H), 2.48-2.41 (m, 2H), 2.20-2.02 (m,2H).

Example 167(R)-4-(3-(3-(azetidin-1-yl)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-onehydrochloride; (I-167) Step 1: Preparation of(R)-4-(3-(3-(azetidin-1-yl)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-onehydrochloride

This compound was made using the procedure described for example 156(Step 1). Thus, the intermediate compound (example 135)(R)-4-(3-(3-(azetidin-1-yl)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(100 mg, 0.24 mmol) was reacted with 1N solution of hydrochloric acid(0.48 mL, 0.48 mmol) to afford the title compound (99 mg, 93%).

¹H-NMR (DMSO, 400 MHz): δ 12.61 (s, 1H), 9.23 (d, 2H), 8.26 (d, 1H),7.96 (t, 1H), 7.91-7.80 (m, 2H), 7.46-7.35 (m, 1H), 7.25-7.18 (m, 1H),4.33 (s, 2H), 3.73-3.58 (m, 1H), 3.44-3.39 (m, 1H), 3.27-3.19 (m, 1H),3.13-3.08 (m, 1H), 2.98 (t, 1H), 2.86 (d, 1H), 2.77-2.61 (m, 1H), 2.16(t, 2H), 2.03 (t, 2H), 1.77-1.62 (m, 2H).

Example 1684-(4-fluoro-3-(3-(pyrrolidin-1-ylethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-onehydrochloride; (I-168) Step 1: Preparation of4-(4-fluoro-3-(3-(pyrrolidin-1-ylmethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-onehydrochloride

This compound was made using the procedure described for example 156(Step 1). Thus, the intermediate compound (example140)-(4-fluoro-3-(3-(pyrrolidin-1-ylmethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one(100 mg, 0.23 mmol) was reacted with 1N solution of hydrochloric acid(0.46 mL, 0.46 mmol) to afford the title compound (96 mg, 91%).

¹H-NMR (CDCl₃, 400 MHz): δ 9.85 (s, 1H), 9.19 (d, 2H), 8.46-8.44 (m,1H), 7.78-7.70 (m, 3H), 7.49-7.47 (m, 1H), 7.32-7.27 (m, 1H), 7.03-6.98(m, 1H), 4.29-4.24 (m, 3H), 4.14-4.10 (t, 1H), 3.85-3.77 (m, 2H),2.91-2.64 (m, 3H), 2.48 (s, 4H), 1.77 (s, 4H).

Example 1694-(4-fluoro-3-(3-(piperidin-1-ylmethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-onehydrochloride; (I-169) Step 1: Preparation of4-(4-fluoro-3-(3-(piperidin-1-ylmethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-onehydrochloride

This compound was made using the procedure described for example 156(Step 1). Thus, the intermediate compound (example 142)4-(4-fluoro-3-(3-(piperidin-1-ylmethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one(100 mg, 0.23 mmol) was reacted with 1N solution of hydrochloric acid(0.46 mL, 0.46 mmol) to afford the title compound (105 mg, 97%).

¹H-NMR (CDCl₃, 400 MHz): δ 9.94 (s, 1H), 9.19 (d, 2H), 8.46 (m, 1H),7.78-7.70 (m, 3H), 7.50-7.48 (m, 1H), 7.31-7.27 (m, 1H), 7.01 (t, 1H),4.27-4.23 (t, 1H), 4.26 (s, 2H), 7.13-4.09 (t, 1H), 3.83-3.70 (m, 2H),2.88-2.84 (m, 1H), 2.57-2.55 (m, 2H), 2.32 (s, 4H), 1.54 (s, 4H), 1.42(s, 2H).

Example 1704-(3-(3-(azetidin-1-ylmethyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-onehydrochloride; (I-170) Step 1: Preparation of4-(3-(3-(azetidin-1-ylmethyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-onehydrochloride

This compound was made using the procedure described for example 156(Step 1). Thus, the intermediate compound (example 143)4-(3-(3-(azetidin-1-ylmethyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(100 mg, 0.24 mmol) was reacted with 1N solution of hydrochloric acid(0.48 mL, 0.48 mmol) to afford the title compound (101 mg, 95%).

¹H-NMR (400 MHz, MeOD): δ 8.36 (d, 1H), 7.94 (d, 1H), 7.84 (m, 2H), 7.50(m, 2H), 7.13 (t, 1H), 4.38 (s, 2H), 4.19 (t, 1H), 4.09 (m, 1H), 3.74(m, 2H), 3.30 (m, 4H), 2.69 (m, 3H), 2.14 (t, 2H).

Example 1714-(3-(3-((cyclopropylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-onehydrochloride; (I-171) Step 1: Preparation of4-(3-(3-((cyclopropylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-onehydrochloride

This compound was made using the procedure described for example 156(Step 1). Thus, the intermediate compound (example 25)4-(3-(3-((cyclopropylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(100 mg, 0.25 mmol) was reacted with 1N solution of hydrochloric acid(0.50 mL, 0.50 mmol) to afford the title compound (99 mg, 91%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.03 (s, 1H), 9.18 (d, 2H), 8.47-8.45 (m,1H), 7.80-7.71 (m, 3H), 7.52-7.48 (m, 1H), 7.32-7.28 (m, 1H), 7.01 (t,1H), 4.27 (s, 2H), 4.26-4.22 (m, 1H), 4.10 (t, 1H), 3.85-3.81 (m, 1H),3.73-3.70 (m, 1H), 2.99-2.88 (m, 2H), 2.81-2.72 (m, 1H), 2.07 (m, 1H),1.57 (br, 1H), 0.45-0.41 (m, 2H), 0.29-0.26 (m, 2H).

Example 1724-(4-fluoro-3-(3-((isopropylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-onehydrochloride; (I-172) Step 1: Preparation of4-(4-fluoro-3-(3-((isopropylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-onehydrochloride

This compound was made using the procedure described for example 156(Step 1). Thus, the intermediate compound (example 145)4-(4-fluoro-3-(3-((isopropylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one(100 mg, 0.24 mmol) was reacted with 1N solution of hydrochloric acid(0.48 mL, 0.48 mmol) to afford the title compound (95 mg, 89%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.20 (br, 1H), 9.19 (d, 2H), 8.47-8.45 (m,1H), 7.80-7.70 (m, 3H), 7.51-7.49 (dd, 1H), 7.32-7.28 (m, 1H), 7.01 (t,1H), 4.27 (s, 2H), 4.28-4.23 (m, 1H), 4.12 (t, 1H), 3.84-3.81 (dd, 1H),3.75-3.71 (dd, 1H), 2.88-2.69 (m, 4H), 1.05-1.03 (dd, 6H).

Example 1734-(3-(3-(((cyclopropyl)ethyl)amino)ethyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-onehydrochloride; (I-173) Step 1: Preparation of4-(3-(3-(((cyclopropylmethyl)amino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-onehydrochloride

This compound was made using the procedure described for example 156(Step 1). Thus, the intermediate compound (example 146)4-(3-(3-(((cyclopropylmethyl)amino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(100 mg, 0.23 mmol) was reacted with 1N solution of hydrochloric acid(0.46 mL, 0.46 mmol) to afford the title compound (94 mg, 90%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.36 (br, 1H), 9.18 (d, 2H), 8.47-8.45 (m,1H), 7.80-7.71 (m, 3H), 7.51-7.49 (m, 1H), 7.32-7.28 (m, 1H), 7.01 (t,1H), 4.27-4.24 (m, 3H), 4.13 (t, 1H), 3.86-3.75 (m, 2H), 2.94-2.75 (m,3H), 2.48-2.46 (dd, 2H), 1.61 (br, 1H), 0.95-0.91 (m, 1H), 0.51-0.46 (m,2H), 0.12-0.09 (m, 2H).

Example 1744-(4-fluoro-3-(3-((isobutylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-onehydrochloride; (I-174) Step 1: Preparation of4-(4-fluoro-3-(3-((isobutylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-onehydrochloride

This compound was made using the procedure described for example 156(Step 1). Thus, the intermediate compound (example 147)4-(4-fluoro-3-(3-((isobutylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one(100 mg, 0.23 mmol) was reacted with 1N solution of hydrochloric acid(0.46 mL, 0.46 mmol) to afford the title compound (101 mg, 93%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.69 (br, 1H), 9.20 (d, 2H), 8.47-8.45 (m,1H), 7.80-7.71 (m, 3H), 7.50-7.48 (m, 1H), 7.32-7.28 (m, 1H), 7.00 (t,1H), 4.27-4.23 (m, 3H), 4.14 (t, 1H), 3.86-3.78 (m, 2H), 2.93-2.78 (m,3H), 2.45 (s, 1H), 2.44 (s, 1H), 1.81-1.71 (m, 1H), 0.91 (s, 3H), 0.89(s, 3H).

Example 1754-(3-(3-((cyclobutylamino)ethyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-onehydrochloride; (I-175) Step 1: Preparation of4-(3-(3-((cyclobutylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-onehydrochloride

This compound was made using the procedure described for example 156(Step 1). Thus, the intermediate compound (example 149)4-(3-(3-((cyclobutylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one(100 mg, 0.24 mmol) was reacted with 1N solution of hydrochloric acid(0.48 mL, 0.48 mmol) to afford the title compound (99 mg, 91%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.33 (br, 1H), 9.19 (d, 2H), 8.47-8.45 (m,1H), 7.80-7.71 (m, 3H), 7.50-7.48 (m, 1H), 7.31-7.28 (m, 1H), 7.00 (t,1H), 4.27-4.22 (m, 3H), 4.11 (t, 1H), 3.83-3.72 (m, 2H), 3.23 (m, 1H),2.83-2.72 (m, 3H), 2.23-2.17 (m, 2H), 1.71-1.62 (m, 5H).

Example 1764-(4-fluoro-3-(3-((prop-2-yn-1-ylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-onehydrochloride; (I-176) Step 1: Preparation of4-(4-fluoro-3-(3-((prop-2-yn-1-ylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-onehydrochloride

This compound was made using the procedure described for example 156(Step 1). Thus, the intermediate compound (example 150)4-(4-fluoro-3-(3-((prop-2-yn-1-ylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one(100 mg, 0.25 mmol) was reacted with 1N solution of hydrochloric acid(0.50 mL, 0.50 mmol) to afford the title compound (96 mg, 88%).

¹H-NMR (CDCl₃, 400 MHz): δ 10.61 (s, 1H), 9.19 (d, 2H), 8.48-8.46 (m,1H), 7.80-7.71 (m, 3H), 7.51-7.49 (m, 1H), 7.32-7.28 (m, 1H), 7.01 (t,1H), 4.28-4.24 (m, 3H), 4.12 (t, 1H), 3.88-3.76 (m, 2H), 3.43 (m, 2H),3.00-2.87 (m, 2H), 2.78-2.72 (m, 1H), 2.27-2.23 (m, 1H), 1.45 (br, 1H).

Experiment 1 In Vitro Test for Antitumoral Activity

To ecaluate the in vitro test, the invented compounds (from I-1 toI-155) were determined as follows and showed table 1, 2, 3, 4 and 5.

1. Determination of Cellular PAR Levels

Cellular PAR assay was performed to measure cellular PARP inhibitoryactivity of the compounds in the present invention. Hela human cervicalcancer cells cultured in Minimum Essential Medium with Earle's BalancedSalts (MEM/EBSS) containing 10% FBS were seeded into 96-well cellculture plates, and incubated for 1 day at 37° C. under 5% CO₂atmosphere. After the invented compounds serially diluted in DMSO wereadded to each well, and then DNA damage was provoked by addition of H₂O₂solution in H₂O. Cellular PAR levels were determined and EC₅₀ wascalculated by using PAR antibody and detection solution.

TABLE 1 EC₅₀ Cellular PAR Compound [EC₅₀, nM] WO2004080976A1 A Example168 I-8 B I-9 B I-10 A I-11 B I-12 A I-13 A I-14 B I-15 C I-16 C I-17 AI-18 A I-19 A I-20 B I-21 B I-22 A I-23 C I-24 C I-25 A I-26 A I-27 AI-28 A I-29 B I-30 B I-31 A I-32 A I-33 A I-34 C I-35 A I-36 B I-37 AI-38 A I-39 B I-40 A I-41 A I-42 A I-43 A I-44 A I-45 A I-46 A I-47 BI-48 A I-49 A I-50 A I-51 A I-52 A I-53 A I-54 A I-55 A I-56 A I-57 AI-58 A I-59 A I-60 B I-61 A I-62 A I-63 B I-64 B I-65 B I-66 A I-67 BI-68 B I-69 A I-70 A I-71 A I-72 C I-73 A I-74 A I-75 A I-76 A I-77 AI-78 B I-79 A I-80 A I-81 A I-82 A I-83 A I-84 B I-85 A I-86 A I-87 BI-88 A I-89 A I-90 A I-91 A I-92 A I-93 B I-94 B I-95 A I-96 C I-97 CI-98 A I-99 A I-100 A I-101 A I-102 A I-103 B I-104 A I-105 A I-106 CI-107 A I-108 B I-109 A I-110 A I-111 B I-112 B I-113 B I-114 B I-115 BI-116 B I-118 B I-119 C I-120 A I-121 C I-122 B I-123 B I-124 B I-125 BI-126 A I-127 C I-128 A I-129 D I-130 A I-131 B I-132 A I-133 B I-134 BI-135 A I-136 A I-137 B I-138 B I-139 B I-140 A I-141 A I-142 A I-143 AI-144 A I-145 A I-146 A I-147 B I-148 A I-149 A I-150 B I-151 B I-152 DI-153 B I-154 A I-155 A Range A: EC₅₀ ≤ 5 nM Range B: 5 nM < EC₅₀ ≤ 50nM Range C: 50 nM < EC₅₀ ≤ 300 nM Range D: 300 nM < EC₅₀ ≤ 1,000 nMRange E: EC₅₀ > 1,000 nM

According to the above table 1, the compounds in the present invent ionshowed potent cellular PARP inhibitory activity in cellular PAR assay.

2. Cell Viability Assay (MDA-MB-436)

Cell viability assay was performed by using MDA-MB-436 cell line tomeasure cytotoxicity of compounds in the present invention. MDA-MB-436breast cancer cell line was seeded into 96-well plates at 37° C. under5% CO₂ atmosphere using DMEM/F12 (Gibco) containing 10% FBS (Hyclone).After 24 hr incubation, cells were treated with the invented compoundsat various concentrations for 6 days. The medium was changed every 3day. 6 days later, A fluorescence reagent was used to determine the IC₅₀values.

TABLE 2 Compound IC₅₀ Compound MDA-MB-436 [nM] WO2004080976A1 B Example168 WO2004080976A1 B Example 168 I-14 C I-19 C I-22 C I-24 D I-25 B I-26B I-27 A I-28 B I-29 D I-30 C I-31 B I-32 A I-33 A I-34 D I-35 A I-36 BI-37 B I-38 B I-39 D I-40 B I-41 A I-42 A I-43 B I-44 A I-45 B I-46 BI-48 A I-49 B I-50 C I-51 B I-52 A I-53 A I-54 B I-55 B I-56 D I-57 BI-58 B I-59 B I-61 C I-66 C I-69 C I-70 C I-71 C I-73 C I-74 B I-75 BI-76 B I-77 C I-78 D I-79 C I-80 A I-81 C I-82 B I-83 B I-84 C I-85 AI-86 B I-87 D I-88 A I-89 B I-90 C I-91 C I-92 B I-93 C I-94 D I-95 CI-96 D I-98 D I-99 B I-100 D I-101 D I-102 D I-103 D I-104 D I-109 DI-110 D I-111 D I-112 D I-113 D I-114 D I-115 D I-116 D I-118 D I-120 AI-121 D I-124 C I-125 A I-126 B I-128 B I-129 D I-130 A I-131 C I-132 AI-133 C I-134 C I-135 B I-136 B I-137 C I-138 D I-140 A I-141 B I-142 BI-143 A I-144 A I-145 B I-146 B I-147 D I-148 A I-149 A I-150 C I-151 DI-153 D I-154 D I-155 C Range A: IC₅₀ ≤ 5 nM Range B: 5 nM < IC₅₀ ≤ 50nM Range C: 50 nM < IC₅₀ ≤ 300 nM Range D: 300 nM < IC₅₀ ≤ 1,000 nMRange E: IC₅₀ > 1,000 nM

According to the above table 2, the compounds in the present invent ionshowed potent growth inhibition of cancer cells in cell cytotoxicityassay using MDA-MB-436 breast cancer cell line.

3. Cell Viability Assay (Capan-1)

Cell viability assay was performed by using Capan-1 cell line to measurecytotoxicity of compounds in the present invention. Capan-1 pancreaticcancer cell line was seeded into 96-well plates at 37° C. under 5% COatmosphere using IMDM (Sigma) containing 10% FBS (Hyclone). After 24 hrincubation, cells were treated with the invented compounds at variousconcentrations for 10 days. After 7-day incubation, the medium waschanged. 10 days later, A fluorescence reagent was used to determine theIC₅₀ values.

TABLE 3 Compound IC₅₀, Compound Capan-1 [nM] WO2004080976A1 D Example168 WO2004080976A1 D Example 168 I-25 D I-26 D I-27 C I-28 D I-31 C I-32C I-33 D I-35 D I-40 D I-36 D I-41 D I-42 D I-43 D I-44 D I-53 D I-80 CI-82 D I-83 D I-132 B I-140 D I-141 D I-142 D I-143 C I-146 D I-149 DI-99 D I-100 D Range A: IC₅₀ ≤ 5 nM Range B: 5 nM < IC₅₀ ≤ 50 nM RangeC: 50 nM < IC₅₀ ≤ 300 nM Range D: 300 nM < IC₅₀ ≤ 1,000 nM Range E:IC₅₀ > 1,000 nM

According to the above table 3, the compounds in the present invent ionshowed potent growth inhibition of cancer cells in cell cytotoxicityassay using Capan-1 pancreatic cancer cell line.

4. Cell Viability Assay (LNCap)

Cell viability assay was performed by using LNCaP cell line to measurecytotoxicity of compounds in the present invention. LNCaP prostatecancer cell line was seeded into 96-well plates at 37° C. under 5% CO₂atmosphere using RPMI-1640 (Hyclone) containing 10% FBS (Hyclone). After24 hr incubation, cells were treated with the invented compounds atvarious concentrations for 11 days. The medium was changed every 3 to 4day. 11 days later, A fluorescence reagent was used to determine theIC₅₀ values.

TABLE 4 Compound IC₅₀ Compound LNCap [nM] WO2004080976A1 E Example 168I-27 C I-32 C I-33 D I-35 E I-53 E I-80 C I-83 E I-99 D I-114 B I-131 BI-146 E I-149 E Range A: IC₅₀ ≤ 5 nM Range B: 5 nM < IC₅₀ ≤ 50 nM RangeC: 50 nM < IC₅₀ ≤ 300 nM Range D: 300 nM < IC₅₀ ≤ 1,000 nM Range E:IC₅₀ > 1,000 nM

According to the above table 4, the compounds in the present invent ionshowed potent growth inhibition of cancer cells in cell cytotoxicityassay using LNCaP prostate cancer cell line.

5. Tankyrase-1 Enzyme Assay

Tankyrase-1 enzyme assay was performed to determine Tankyrase-1inhibitory activity of compounds in the present invention. The enzymaticreaction was conducted by coating the plate with substrates oftankyrase-1, and then the plate was washed. Compounds in the presentinvention serially diluted in DMSO were added to the reaction bufferactivating tankyrase-1, and incubated for 1 hr at room temperature.After stopping the reaction, the plate was washed, and streptavidin-HRPwas added to each well. IC₅₀ calculated by adding chemiluminescentsubstrate and immediately reading the sample in a microplate reader(Biotek).

TABLE 5 Compound IC50 Compound Tankyrase-1 [nM] WO2004080976A1 E Example168 I-27 E I-32 E I-33 E I-99 D I-114 E I-130 C I-147 E I-150 E Range A:IC₅₀ ≤ 5 nM Range B: 5 nM < IC₅₀ ≤ 50 nM Range C: 50 nM < IC₅₀ ≤ 300 nMRange D: 300 nM < IC₅₀ ≤ 1,000 nM Range E: IC₅₀ > 1,000 nM

According to the above table 5, the compounds in the prevent inventionexhibited strong inhibitory activity against tankyrase-1.

Experiment 2 In Vivo Test for Antitumoral Activity

To evaluate the in vivo antitumoral efficacy, the invented compounds(I-80˜171) was determined as a result to follows.

Capan-1 Human pancreatic cancer cells were established as subcutaneousxenografts by injection of 8×10⁶ cells into the flanks of adult femaleBalb/c nude mice. Mice with established tumors (160-250 mm³) wereselected for study (n=6/treatment group). The test compounds wereformulated in DW and administered orally (po) at a dose of 30˜200 mg/kg.The vehicle alone was administered to control groups. Animals were dosed5 days per week (Monday through Friday) for 3 consecutive weeks.

Animals were weighed and tumor size was determined twice weekly bycaliper measurements, and tumor volumes were calculated (volume=[1×w²]/2(mm³), where 1 and w refer to the larger and smaller dimensionscollected at each measurement). The mean tumor volumes of each groupwere calculated. The change in mean treated tumor volume was divided bythe change in mean control tumor volume, multiplied by 100 andsubtracted from 100% to give the tumor growth inhibition for each group.

TABLE 6 Compound Does Schedule % TGI WO2004080976A1 200 mg/kg po qd × 553.5 Example 168 I-80 100 mg/kg po qd × 5 75.9 I-80 200 mg/kg po qd × 5103.9 I-159 100 mg/kg po qd × 5 59.4 I-159 200 mg/kg po qd × 5 69.4I-158 100 mg/kg po qd × 5 44.9 I-158 200 mg/kg po qd × 5 80.9 I-160 100mg/kg po qd × 5 55.8 I-160 200 mg/kg po qd × 5 88.2 I-171  30 mg/kg poqd × 5 42.1 I-171  60 mg/kg po qd × 5 69.7

As can be seen from table 6, the selected compounds showed useful tumorgrowth inhibition.

Experiment 3 Mouse Pharmacokinetics

To ecaluate the pharmacokinetics test, the invented compounds (from I-25to I-1171) were determined as follows. Blood samples are collected at15, 30, 60, 120, 240, 480, 1140 min. Quantification is by using aLC-MS/MS method specific to the selected compound. Pharmarcokineticsparameters are calculated using WinNonLinnon compartmental analysissoftware.

TABLE 7 AUC Compound [min * ng/mL] WO2004080976A1 39,927 Example 168I-25 49,858 I-26 200,772 I-27 28,302 I-30 31,280 I-33 61,268 I-35135,283 I-53 74,937 I-75 28,516 I-80 121,308 I-83 34,044 I-99 35,139I-120 30,582 I-135 9,175 I-140 17,724 I-141 11,588 I-142 5,325 I-14340,367 I-146 65,532 I-148 28,290 I-149 10,138 I-159 28,302 I-160 135,283I-161 61,268 I-171 40,367

As can be seen from table 7, the selected compounds showed significantpharmacokinetics in Balb/c male mice.

Experiment 4 Solubility Test

To evaluate the solubility, the invented compounds (I-159, I-161 andI-171) was determined as follows. The compounds was dissolve in water (1mL, 10 mL and 100 mL) at 25° C. under an atmospheric pressure.

TABLE 8 Solvent by volume for one Compound part of soluble by weight.WO2004080976A1 From 1000 to 10000 mL Very slightly example 168 solubleI-159 From 30 to 100 mL Sparingly soluble I-161 From 30 to 100 mLSparingly soluble I-171 From 30 to 100 mL Sparingly soluble

As can be seen form Table 8. The invented compounds showed significantsolubility.

It will be understood that the invention disclosed and defined in thisspecification extends to all alternative combinations of two or more ofthe individual features mentioned or evident from the text or drawings.All of these different combinations constitute various alternativeaspects of the invention.

INDUSTRIAL APPLICABILITY

The compounds of the present invention are highly active in thesuppression of PARP, and according to its pharmaceutical compositionsare expected to be useful for therapeutic applications which areimproved by suppression of PARP activity, and cancer with mutated BRCA1,BRCA2 and ERG fusion gene in mono or combination treatment withradiation and with chemotherapy.

The invention claimed is:
 1. A compound represented by Formula I, aracemic mixture thereof, an enantiomer thereof, a diastereoisomerthereof, or a pharmaceutically acceptable salt thereof,

Inwherein in the present Formula I, n is 1 or 2,

Whereinwherein, when the R is

m is 0, 1 or 2, L is oxygen, methylene, carbonyl, CONHCH₂, NR^(c1)CH₂,NR^(c2)CO, NR^(c3), CONR^(c4) or CH₂NR^(c5) (especially, R^(c1), whereinR^(c2), R^(c3), R^(c4) and R^(c5) is each independently oxygen,C₁₋₄alkylamine, hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, halo C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, or C₃₋₈ cycloalkyl, R^(X) is hydrogen, cyano,hydroxyl, trifluoromethyl, C₁₋₆ alkyl or C₃₋₈ cycloalkyl methyl, ethylor cyclopropyl, R^(Y) is hydrogen, amide dimethylamide, cyano, hydroxyl,trifluoromethyl, halo, ester ethylester, C₁₋₄ alkylamine, C₁₋₆ alkyl,C₁₋₆ methoxyalkyl or C₂₋₆ alkynyl dimethylamine, methyl, methoxymethylor propargyl, Z is unsubstituted, C₁₋₆ alkyl, C₁₋₆ methoxyalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, C₆₋₁₀aromatic cycle or 3-8 membered heterocycle having 1-3 nitrogens,wherein, when the R is

p and q is each independently from 1 to 3 1 or 2, W is CR^(d1)R^(d2) orNR^(d3) (especially, wherein R^(d1), R^(d2) and R^(d3) is eachindependently hydrogen, fluoro or C₁₋₆ alkyl) methyl, wherein, when theR is

R¹, R² and R³ is each independently hydrogenor C₁₋₆ alkyl, methyl, orethyl.
 2. The compound according to claim 1, wherein, L is methylene,carbonyl, CONHCH₂, NR^(c1)CH₂, NR^(c2)CO, NR^(c3), CONR^(c4) orCH₂NR^(c5) (especially, R^(c1), R^(c2), R^(c3), R^(c4) and R^(c5) iseach independently hydrogen, C₁₋₆alkyl, C₂₋₆ alkynyl or C₃₋₈cycloalkyl), R^(X) is hydrogen, cyano, hydroxyl, trifluoromethyl,methyl, ethyl or cyclopropyl, R^(Y) is hydrogen, dimethylamide, cyano,hydroxyl, trifluoromethyl, halo, ethylester, dimethylamine, methyl,methoxymethyl or propargyl, Z is unsubstituted, C₁₋₆ alkyl, C₁₋₆methoxyalkyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aromatic cycle or 3-8membered heterocycle having 1-3 nitrogens, p and q is each independently1 or 2, W is CR^(d1)R^(d2) or NR^(d3) (especially R^(d1), R^(d2) andR^(d3) is each independently hydrogen, fluoro or methyl), R¹, R² and R³is each independently hydrogen, methyl or ethyl.
 3. The compoundaccording to claim 1, wherein, L is NR^(c1)CH₂, CONR^(c4) or CH₂NR^(c5)(especially, R^(c1), R^(c4) and R^(c5) is each independently hydrogen,methyl, ethyl, propyl, propargyl or cyclopropyl), Z is


4. The compound according to claim 1, wherein, L is methylene orcarbonyl, Z is


5. The compound according to claim 1, wherein, L is CONHCH₂ orNR^(c2)CO(especially, wherein R^(c2) is hydrogen, methyl, ethyl orpropyl), Z is


6. The compound according to claim 1, wherein, the present R is

R is


7. The compound according to claim 1, wherein, the compound representedby Formula I is selected from the group Consisting of the followingcompounds:(R)-4-(3-(3-aminopyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(S)-4-(3-(3-aminopyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;4-(3-(3-aminoazetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(R)-4-(4-fluoro-3-(3-hydroxypyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(S)-4-(4-fluoro-3-(3-hydroxypyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-hydroxyazetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-(hydroxymethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(R)—N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)cyclopropanecarboxamide;N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)cyclopropanecarboxamide;(S)—N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)cyclopropanecarboxamide;(R)—N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)-N-methylcyclopropanecarboxamide;N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)-N-methylcyclopropanecarboxamide;(S)—N-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)-N-methylcyclopropanecarboxamide;3-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)-5,5-dimethylimidazolidine-2,4-dione;(R)-3-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)imidazolidine-2,4-dione;(R)-1-ethyl-3-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)imidazolidine-2,4-dione;4-(4-fluoro-3-(3-(4-fluoropiperidine-1-carbonyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(3-(3-(3,3-difluoroazetidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;4-(3-(3-(3,3-difluoropyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;4-(3-(3-(3,3-difluoropyrrolidine-1-carbonyl)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(R)—N-(cyclopropylmethyl)-1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidine-3-carboxamide;4-(4-fluoro-3-(3-(pyrrolidine-1-carbonyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(R)-4-(3-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(S)-4-(3-(3-(3-(dimethylamino)pyrrolidine-1-carbonyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;4-(3-(3-(cyclobutylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;4-(3-(3-(cyclopropylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;4-(3-(3-(cyclopentylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;4-(3-(3-(cyclohexylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(R)-4-(3-(3-(cyclopropylamino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(R)-4-(3-(3-(cyclobutylamino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(R)-4-(3-(3-(cyclopentylamino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-(isopropylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(3-(3-((cyclopropylmethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;4-(3-(3-(bis(cyclopropylmethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-(isobutylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-((1-hydroxypropan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-(neopentylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(3-(3-((2,2-dimethylcyclopentyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;ethyl2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)cyclopent-1-enecarboxylate;4-(4-fluoro-3-(3-(pentan-3-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-((3-methylbutan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(3-(3-((1-cyclopropylethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;4-(3-(3-(bicyclo[2.2.1]heptan-2-ylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;4-(3-(3-(sec-butylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;4-(3-(3-((dicyclopropylmethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-((4-methylpentan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-((3-hydroxybutan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-(pentan-2-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-((1-(1-methylcyclopropyl)ethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-((3,3,3-trifluoro-2-methylpropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(3-(3-(allylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-(isopentylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(3-(3-(butylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-((3-methylbut-2-en-1-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(3-(3-((cyclopentylmethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-((4,4,4-trifluorobutyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-(pentylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(3-(3-((2-cyclopropylethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-(propylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-(methyl(pyridin-4-ylmethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(R)-4-(4-fluoro-3-(3-(methyl(pyridin-4-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(S)-4-(4-fluoro-3-(3-(methyl(pyridin-4-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(S)-4-(4-fluoro-3-(3-(methyl(pyridin-2-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(R)-4-(4-fluoro-3-(3-(methyl(pyridin-2-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-(methyl(pyridin-2-ylmethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-(methyl(pyridin-3-ylmethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(S)-4-(4-fluoro-3-(3-(methyl(pyridin-3-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(R)-4-(4-fluoro-3-(3-(methyl(pyridin-3-ylmethyl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(3-(3-(cyclopropyl(methyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;4-(3-(3-(cyclopropyl(ethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;4-(3-(3-(cyclobutyl(methyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;4-(3-(3-(cyclopentyl(prop-2-yn-1-yl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;4-(3-(3-(3,3-difluoropyrrolidin-1-yl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-(4-fluoropiperidin-1-yl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(3-([1,3′-biazetidine]-1′-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-(pyrrolidin-1-yl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-(piperidin-1-yl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-(4-methylpiperazin-1-yl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-(phenylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-((1-(trifluoromethyl)cyclopropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-(prop-2-yn-1-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(S)-4-(4-fluoro-3-(3-((1-methoxypropan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(R)-4-(4-fluoro-3-(3-((1-methoxypropan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-((1-(hydroxymethyl)cyclopropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-((1-methylcyclopropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(R)-4-(3-(3-((3,3-dimethylbutan-2-yl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(S)-4-(3-(3-((3,3-dimethylbutan-2-yl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(R)-4-(4-fluoro-3-(3-((3-methylbutan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(S)-4-(4-fluoro-3-(3-((3-methylbutan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-((1-(methoxymethyl)cyclopropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(3-(3-(but-3-yn-1-ylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-((2-methylallyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-((3-hydroxy-2,2-dimethylpropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;1-(((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)methyl)cyclopropanecarbonitrile;4-(4-fluoro-3-(3-((2,2,2-trifluoroethyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(R)-4-(4-fluoro-3-(3-(pyrrolidin-3-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(S)-4-(4-fluoro-3-(3-(pyrrolidin-3-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;1-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)cyclopentanecarbonitrile;1-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)cyclobutanecarbonitrile;2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)propanenitrile;2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)butanenitrile;2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)-3-methylbutanenitrile;2-cyclopropyl-2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)acetonitrile;4-(4-fluoro-3-(3-((1-(trifluoromethyl)cyclobutyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(S)-4-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(S)-4-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-(methyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-(pyrimidin-2-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(S)-4-(4-fluoro-3-(3-(pyrimidin-2-ylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(S)-4-(3-(3-((6-chloropyridazin-3-yl)(methyl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(S)-4-(3-(3-((6-chloropyridazin-3-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(S)-4-(4-fluoro-3-(3-(methyl(pyridazin-3-yl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(3-(3-((6-chloropyridazin-3-yl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;4-(3-(3-((6-chloropyridazin-3-yl)(methyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;4-(3-(3-(cyclobutyl(pyrimidin-2-yl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-(pyridazin-3-ylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(R)-4-(3-(3-((6-chloropyridazin-3-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(R)-4-(3-(3-((6-chloropyridazin-3-yl)(methyl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(R)-4-(4-fluoro-3-(3-(pyrimidin-2-ylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(R)-4-(3-(3-(methyl(pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(R)-4-(4-fluoro-3-(3-(pyridazin-3-ylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(R)-4-(4-fluoro-3-(3-(methyl(pyridazin-3-yl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(R)-4-(4-fluoro-3-(3-(thiazol-2-ylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(R)-4-(3-(3-((5-ethynylpyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(R)-2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)amino)pyrimidine-5-carbonitrile;(R)-2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)amino)nicotinonitrile;(R)-4-(4-fluoro-3-(3-(pyridin-2-ylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(R)-2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pyrrolidin-3-yl)amino)-N,N-dimethylnicotinamide;(R)-4-(3-(3-((5-bromopyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(R)-4-(4-fluoro-3-(3-((5-(trifluoromethyl)pyridin-2-yl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(R)-4-(4-fluoro-3-(3-((4-(trifluoromethyl)pyridin-2-yl)amino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(3-(3-(benzylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-((3,3,3-trifluoropropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(R)-4-(3-(3-(azetidin-1-yl)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(R)-4-(3-([1,3′-bipyrrolidine]-1′-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(R)-4-(4-fluoro-3-(3-(piperidin-1-yl)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(R)-4-(4-fluoro-3-(3-(p-tolylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;(R)-4-(4-fluoro-3-(3-(phenylamino)pyrrolidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-(pyrrolidin-1-ylmethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-(piperidin-1-ylmethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(3-(3-(azetidin-1-ylmethyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;4-(3-(3-((cyclopropylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-((isopropylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(3-(3-(((cyclopropylmethyl)amino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-((isobutylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(3-(3-((tert-butylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;4-(3-(3-((cyclobutylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-((prop-2-yn-1-ylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-((phenylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;1-((((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)methyl)amino)methyl)cyclopropanecarbonitrile;1-(((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)methyl)amino)cyclopropanecarbonitrile;4-(3-(3-((cyclopropyl(prop-2-yn-1-yl)amino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;4-(3-(3-((cyclopropyl(methyl)amino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;4-(3-(3-((cyclopropyl(ethyl)amino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;4-(3-(3-(cyclobutylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-onehydrochloride;4-(3-(3-(cyclopropylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-onehydrochloride;4-(3-(3-(cyclopentylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-onehydrochloride;4-(4-fluoro-3-(3-(isopropylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-onehydrochloride;4-(3-(3-((cyclopropylmethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-onehydrochloride;4-(4-fluoro-3-(3-(isobutylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-onehydrochloride;4-(4-fluoro-3-(3-((1-hydroxypropan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-onehydrochloride;4-(3-(3-(butylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-onehydrochloride;4-(3-([1,3′-biazetidine]-1′-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-onehydrochloride;(R)-4-(4-fluoro-3-(3-((1-methoxypropan-2-yl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-onehydrochloride;1-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)azetidin-3-yl)amino)cyclobutanecarbonitrilehydrochloride;(R)-4-(3-(3-(azetidin-1-yl)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-onehydrochloride;4-(4-fluoro-3-(3-(pyrrolidin-1-ylmethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-onehydrochloride;4-(4-fluoro-3-(3-(piperidin-1-ylmethyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-onehydrochloride;4-(3-(3-(azetidin-1-ylmethyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-onehydrochloride;4-(3-(3-((cyclopropylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-onehydrochloride;4-(4-fluoro-3-(3-((isopropylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-onehydrochloride;4-(3-(3-(((cyclopropylmethyl)amino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-onehydrochloride;4-(4-fluoro-3-(3-((isobutylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-onehydrochloride;4-(3-(3-((cyclobutylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-onehydrochloride; and4-(4-fluoro-3-(3-((prop-2-yn-1-ylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-onehydrochloride.
 8. A compound, a racemic mixture thereof, an enantiomerthereof, a diastereoisomer thereof, or a pharmaceutically acceptablesalt thereof, selected from the group consisting of the following:4-(3-(3-(cyclopentylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(R)-4-(3-(3-(cyclopropylamino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;(R)-4-(3-(3-(cyclopentylamino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-(isopropylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(3-(3-((cyclopropylmethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-(isobutylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-((-1-(trifluoromethyl)cyclopropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(3-(3-((cyclopropylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;4-(4-fluoro-3-(3-((isopropylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one;4-(3-(3-(((cyclopropylmethyl)amino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one;and4-(3-(3-((cyclobutylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one.9. The compound according to claim 8, wherein the compound is4-(3-(3-(cyclopentylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one,or a pharmaceutically acceptable salt thereof.
 10. The compoundaccording to claim 8, wherein the compound is(R)-4-(3-(3-(cyclopropylamino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one,or a pharmaceutically acceptable salt thereof.
 11. The compoundaccording to claim 8, wherein the compound is(R)-4-(3-(3-(cyclopentylamino)pyrrolidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one,or a pharmaceutically acceptable salt thereof.
 12. The compoundaccording to claim 8, wherein the compound is4-(4-fluoro-3-(3-(isopropylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one,or a pharmaceutically acceptable salt thereof.
 13. The compoundaccording to claim 8, wherein the compound is4-(3-(3-((cyclopropylmethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one,or a pharmaceutically acceptable salt thereof.
 14. The compoundaccording to claim 8, wherein the compound is4-(4-fluoro-3-(3-(isobutylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one,or a pharmaceutically acceptable salt thereof.
 15. The compoundaccording to claim 8, wherein the compound is4-(4-fluoro-3-(3-((1-(trifluoromethyl)cyclopropyl)amino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one,or a pharmaceutically acceptable salt thereof.
 16. The compoundaccording to claim 8, wherein the compound is4-(3-(3-((cyclopropylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one,or a pharmaceutically acceptable salt thereof.
 17. The compoundaccording to claim 8, wherein the compound is4-(4-fluoro-3-(3-((isopropylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-one,or a pharmaceutically acceptable salt thereof.
 18. The compoundaccording to claim 8, wherein the compound is4-(3-(3-(((cyclopropylmethyl)amino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one,or a pharmaceutically acceptable salt thereof.
 19. The compoundaccording to claim 8, wherein the compound is4-(3-(3-((cyclobutylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one,or a pharmaceutically acceptable salt thereof.
 20. The compoundaccording to claim 8, wherein the compound is4-(3-(3-(cyclopentylamino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-onehydrochloride.
 21. The compound according to claim 8, wherein thecompound is4-(4-fluoro-3-(3-(isopropylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-onehydrochloride.
 22. The compound according to claim 8, wherein thecompound is4-(3-(3-((cyclopropylmethyl)amino)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-onehydrochloride.
 23. The compound according to claim 8, wherein thecompound is4-(4-fluoro-3-(3-(isobutylamino)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-onehydrochloride.
 24. The compound according to claim 8, wherein thecompound is4-(3-(3-((cyclopropylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-onehydrochloride.
 25. The compound according to claim 8, wherein thecompound is4-(4-fluoro-3-(3-((isopropylamino)methyl)azetidine-1-carbonyl)benzyl)phthalazin-1(2H)-onehydrochloride.
 26. The compound according to claim 8, wherein thecompound is4-(3-(3-(((cyclopropylmethyl)amino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-onehydrochloride.
 27. The compound according to claim 8, wherein thecompound is4-(3-(3-((cyclobutylamino)methyl)azetidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-onehydrochloride.
 28. A pharmaceutical composition comprising the compoundof claim 8 and a pharmaceutically acceptable excipient.
 29. Apharmaceutical composition comprising the compound of claim 16 and apharmaceutically acceptable excipient.
 30. A pharmaceutical compositioncomprising the compound of claim 24 and a pharmaceutically acceptableexcipient.
 31. A method of inhibiting growth of a tumor associated withcancer in a subject, comprising administering a therapeuticallyeffective amount of the pharmaceutical composition of claim 28 to thesubject.
 32. The method according to claim 31, wherein the cancer iscaused by a defect of BRCA1, BRCA2, and ERG fusion gene.
 33. The methodaccording to claim 32, wherein the cancer is selected from the groupconsisting of breast cancer, ovarian cancer, pancreatic cancer, gastriccancer, lung cancer, colorectal cancer, brain tumor, prostate cancer andEwings sarcoma.
 34. A method of inhibiting growth of a tumor associatedwith cancer in a subject, comprising administering a therapeuticallyeffective amount of the pharmaceutical composition of claim 29 to thesubject.
 35. The method according to claim 34, wherein the cancer iscaused by a defect of BRCA1, BRCA2, and ERG fusion gene.
 36. The methodaccording to claim 35, wherein the cancer is selected from the groupconsisting of breast cancer, ovarian cancer, pancreatic cancer, gastriccancer, lung cancer, colorectal cancer, brain tumor, prostate cancer andEwings sarcoma.
 37. A method of inhibiting growth of a tumor associatedwith cancer in a subject, comprising administering a therapeuticallyeffective amount of the pharmaceutical composition of claim 30 to thesubject.
 38. The method according to claim 37, wherein the cancer iscaused by a defect of BRCA1, BRCA2, and ERG fusion gene.
 39. The methodaccording to claim 38, wherein the cancer is selected from the groupconsisting of breast cancer, ovarian cancer, pancreatic cancer, gastriccancer, lung cancer, colorectal cancer, brain tumor, prostate cancer andEwings sarcoma.